ライフサイエンスコーパス: Keap1

1 protein Kelch-like-ECH-associated protein 1 (Keap1).

2 ction between endogenous DPP3 and endogenous KEAP1.

3 ved in the degradation of the Nrf2 inhibitor Keap1.

4 tivators, or to ablation of Nrf2's inhibitor Keap1.

5 nd mutants of mVP24 defective for binding to Keap1.

6 -kappaB pathway through its interaction with Keap1.

7 1 enhanced IKKbeta levels in the presence of Keap1.

8 limiting the repressive activity of nuclear KEAP1.

9 re BTB-BACK-Kelch domain proteins, including KEAP1.

10 s degradation in the nucleus, independent of Keap1.

11 a switch in polyubiquitination from Nrf2 to Keap1.

12 d at post-translational regulation points by Keap1.

13 nstance, mutations in the negative regulator KEAP1.

14 hat upon re-expression, miR-200a targets the Keap1 3'-untranslated region (3'-UTR), leading to Keap1

15 transcript levels: TP53 (18%); CTNNB1 (10%); KEAP1 (8%); C16orf62 (8%); MLL4 (7%); and RAC2 (5%).

16 tion of Kelch-like ECH-associated protein 1 (Keap1), a Cullin-3/Rbx1 ubiquitin ligase substrate adapt

17 ions in Kelch-like ECH-associated protein-1 (Keap1), a gene that encodes a joint adaptor and substrat

18 dimeric Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor protein for Cullin3/RING-box

19 tion and sequestration of proteins including Keap1, a negative regulator of antioxidant response.

20 Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated th

21 r accumulation of Nrf2 and downregulation of Keap1, a negative regulator of Nrf2.

22 rgeted by an E3 ubiquitin ligase composed of KEAP1, a PALB2-interacting protein, in complex with cull

23 ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase.

24 f the different NADPH-oxidase subunits, Nrf2-Keap1 activation, gene expression of the antioxidant enz

25 Taken together, we propose that Keap1 acts as a negative regulator for the control of in

26 However, in addition to Nrf2, Keap1 affects ubiquitination of other proteins in the ca

27 nt binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to mo

28 The interaction of mVP24 with Keap1 also relieved Keap1 repression of NF-kappaB report

29 Guided by this information, we identified KEAP1 (also known as KLHL19), the primary negative regul

30 In addition, loss of KEAP1 altered cell metabolism to allow cells to prolifer

31 ole for Kelch-like ECH-associated protein 1 (Keap1), an oxidative stress sensor, in regulating inflam

32 ze to one of its two binding interfaces with KEAP1, an E3 ubiquitin ligase that promotes proteasome-d

33 , we show that PALB2 directly interacts with KEAP1, an oxidative stress sensor that binds and repress

34 The designed antibodies bind to Keap1 and block the Keap1-Nrf2 interaction in an epitope

35 , such as DPP3, which has been shown to bind KEAP1 and enhance NRF2 function upon overexpression.

36 were used to examine the interaction between Keap1 and IKKbeta in the presence of wild-type mVP24 and

37 ants did not disrupt the interaction between Keap1 and IKKbeta.

38 tion factor Nrf2 and its negative regulator, Keap1 and is able to up-regulate the expression of autop

39 The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multip

40 This interaction between Keap1 and mVP24 occurs through the Kelch interaction loo

41 els of IKKbeta expression in the presence of Keap1 and mVP24.

42 eostatic conditions, the interaction between Keap1 and Nrf2 follows a cycle in which the complex sequ

43 d a high-fat diet (HFD) to determine whether Keap1 and Nrf2 impact HFD-induced obesity.

44 strengthen the genetic interactions between KEAP1 and NRF2 in cancer and provide new insight into KE

45 his feature disrupts the interaction between Keap1 and Nrf2.

46 and V155F mutations augmented the binding of KEAP1 and NRF2.

47 ry of 4-hydroxynonenal (HNE) to the proteins Keap1 and PTEN.

48 ilarly show increased cytoplasmic binding of KEAP1 and RBM45.

49 at MCM3 is a point of direct contact between KEAP1 and the MCM hexamer.

50 following alterations in the Nrf2 suppressor Keap1 and the subsequent changes in Nrf2 signaling.

51 differential regulation of NRF1 and NRF2 by KEAP1 and their different physiological roles.

52 ulators Kelch-like ECH-Associated Protein 1 (Keap1) and beta-transducin repeat-containing protein (be

53 ibitor, Kelch like-ECH-associated protein 1 (Keap1), and moves to the nucleus to regulate the transcr

54 hich exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in ce

55 of autophagosomes and sequestration of p62, Keap1, and LC3.

56 ve oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase.

57 WTX and NRF2 compete for binding to KEAP1, and thus loss of WTX leads to rapid ubiquitinatio

58 se to TLR agonists independently of the Nrf2-Keap1 anti-oxidant pathway.

59 further show that tumor-derived mutations in KEAP1 are hypomorphic with respect to NRF2 inhibition an

60 between Nrf2 and its main negative regulator Keap1 are potential pharmacological agents for a range o

61 The results document Keap1 as a promiscuous electrophile-responsive sensor ab

62 The present study identifies KEAP1 as the downstream redox target that contributes to

63 We show evidence of a mechanism whereby Keap1, as part of an E3 ubiquitin ligase complex with Cu

64 By using confocal microscopy, we found that Keap1 associated with mycobacterial phagosomes in a time

65 Moreover, KEAP1 associates with chromatin in a cell cycle-dependen

66 trate of OGT We show that O-GlcNAcylation of KEAP1 at serine 104 is required for the efficient ubiqui

67 ignaling, the NF-kappaB pathway and the NRF2-KEAP1 axis, and offer novel insights into the potential

68 es of tumors due to deregulation of the Nrf2-Keap1 axis, which leads to constitutive activation of Nr

69 hares with NRF2 a highly conserved ETGE-type KEAP1 binding motif and can effectively compete with NRF

70 frequent, missense, and located in the Nrf2-Keap1 binding region.

71 emonstrate that CDK20 competes with NRF2 for KEAP1 binding, enhances the transcriptional activity of

72 if and can effectively compete with NRF2 for KEAP1 binding.

73 ear factor erythroid 2-related factor 2) for Keap1 binding.

74 Here, we report that KEAP1 binds to the Neh2-like (Neh2L) domain of NRF1 and

75 PML-NBs did not contain biologically active Keap1 but contained modified Nrf2 as well as RING finger

76 expression levels of Nrf2 and its inhibitor Keap1 but not through their somatic mutation.

77 ion via Kelch-like ECH-associated protein 1 (Keap1), but how Nrf2 is regulated at the translational l

78 increased retinal Nrf2 and its binding with Keap1, but decreased DNA-binding activity of Nrf2 and al

79 Modification of the sensor protein Keap1 by electrophiles such as the isothiocyanate sulfor

80 d Parkinson's, utilizing the modification of Keap1 by electrophiles, compounds that would not normall

81 Thus, regulation of Nrf2-Keap1 by pharmacological or molecular means could serve

82 iquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DL

83 fic antibody binding with the target protein Keap1, by grafting pre-defined structural interaction pa

84 in human lung A549 cells that contain mutant Keap1, by inhibition of the phosphoinositide 3-kinase (P

85 d tert-butylhydroquinone (tBHQ) depends upon Keap1-C151 and not p62 (the canonical mechanism).

86 ubiquitylation and degradation of NRF2 in a KEAP1-C151 dependent manner; intraperitoneal (IP) inject

87 , whereas NRF2 is dramatically stabilized in KEAP1(-/-) cells.

88 ay by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, with the aid of the heterodimeric

89 conditions, Nrf2 is polyubiquitinated by the Keap1-Cul3 E3 ligase and degraded by the 26S proteasome.

90 deubiquitinated Keap1 incorporates into the Keap1-Cul3-E3 ligase complex more efficiently, enhancing

91 We show that MCM3 is ubiquitylated by the KEAP1-CUL3-RBX1 complex in cells and in vitro Using ubiq

92 nd identify MCM3 as a novel substrate of the KEAP1-CUL3-RBX1 E3 ligase.

93 s, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and is targe

94 Ubiquitylation of Nrf2 by the Keap1-Cullin3/RING box1 (Cul3-Rbx1) E3 ubiquitin ligase

95 quitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compound

96 diator IQGAP1 in lung cancer cell lines with Keap1 deficiency and high RSPO3-LGR4 expression led to r

97 a driving mechanism in the aggressiveness of Keap1-deficient lung ADs.

98 mutual affinity and interaction, leading to Keap1 degradation and Nrf2 activation.

99 s with correct spacing are insufficient as a KEAP1 degron.

100 remnant profiling, we identify the sites of KEAP1-dependent ubiquitylation in MCM3, and these sites

101 " in which Nrf2 binds to both members of the Keap1 dimer.

102 RF2 activation through cell lineage-specific Keap1 disruption (i.e., in T cells, myeloid cells, and d

103 Drosophila Keap1 (dKeap1)-CncC complexes localized to the nucleus a

104 Unexpectedly, we determined that KEAP1 does not regulate total MCM3 protein stability or

105 The interaction of mVP24 with Keap1 enhanced IKKbeta levels in the presence of Keap1.

106 he activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound 2-cyano-3,1

107 c therapy can restore miR-200a regulation of Keap1 expression, therefore reactivating the Nrf2-depend

108 r the activation of Nrf2 by the silencing of Keap1 expression.

109 little is known concerning the regulation of Keap1 expression.

110 constitutive activation of Nrf2 signaling in Keap1(F/F)::AlbCre mice.

111 Here, we generated Keap1(flox/flox) SKH-1 hairless mice in which Nrf2 is di

112 rf2(-/-) mice are much greater than in their Keap1(flox/flox)/Nrf2(+/+) counterparts, establishing Nr

113 multiplicity and burden of cSCC that form in Keap1(flox/flox)/Nrf2(-/-) mice are much greater than in

114 -1 hairless mice in which Nrf2 is disrupted (Keap1(flox/flox)/Nrf2(-/-)) and subjected them chronical

115 ich Nrf2 interacts with a single molecule of Keap1, followed by "closed," in which Nrf2 binds to both

116 aintained at low levels as it is targeted by KEAP1 for ubiquitination and proteasome-mediated degrada

117 XNRD1 and AKT inhibitors relied on wild-type KEAP1 function.

118 Our aim is to understand the role of Nrf2-Keap1-GCLC in the development of diabetic retinopathy.

119 Effect of diabetes on Nrf2-Keap1-GCLC pathway, and subcellular localization of Nrf2

120 Similar impairments in Nrf2-Keap1-GCLC were observed in the endothelial cells expose

121 mors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1

122 duction related genes, MnSOD, CuZnSOD, Nrf2, Keap1, GPx4 and Catalase was also examined.

123 eneral features of the regulation of Nrf2 by Keap1 have been outlined.

124 y regulate its action after its release from Keap1 have received little attention.

125 r NRF2 is considered the primary function of KEAP1; however, few other KEAP1 substrates have been ide

126 We show that loss of Keap1 hyperactivates NRF2 and promotes KRAS-driven LUAD

127 me in kidney disease, we describe the use of Keap1 hypomorphic mice, which possess Nrf2 hyperactivati

128 he suppression was attenuated or reversed in Keap1 hypomorphs, suggesting that protection in these mi

129 Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus

130 icantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, pho

131 eveal a novel redox-mediated modification of KEAP1 in controlling the differential effect of partheno

132 ontrast, parthenolide increases oxidation of KEAP1 in normal prostate epithelial cells, leading to in

133 vestigating the interaction between Nrf2 and Keap1 in single live cells.

134 We demonstrated that deubiquitinated Keap1 incorporates into the Keap1-Cul3-E3 ligase complex

135 manner, whereas siRNA-mediated knockdown of Keap1 increased M. avium-induced expression of inflammat

136 ucleo-cytoplasmic concentration of Nrf2 in a Keap1 independent manner resulting in inefficient transa

137 response mechanism is described based on the Keap1-independent Nuclear Factor-erythroid 2-related fac

138 ts indicated that RAC1 regulation of NRF2 is KEAP1-independent.

139 ere used to determine the effect of mVP24 on Keap1-induced repression of activity.

140 Keap1 inhibition increased Nrf2 nuclear translocation, i

141 edox dysregulation, which can be restored by Keap1 inhibition.

142 activation than the most active noncovalent Keap1 inhibitor known to date.

143 The use of KEAP1-insensitive NRF2 mutants indicated that RAC1 regul

144 of its own promoter region and deficiency in Keap1 instead of gene fusion as in colon cancer.

145 Our targeted investigation of KEAP1-interacting proteins revealed MCM3, an essential s

146 Comparing the spectrum of KEAP1-interacting proteins with the genomic profile of 1

147 oes not interact directly with DmKeap1 via a KEAP1-interacting region motif; nor does ectopically exp

148 Daily administration of PTS disturbed Nrf2/Keap1 interaction and reduced complemented luciferase si

149 We further show that the DPP3-KEAP1 interaction is strongly induced by hydrogen peroxi

150 an ETGE amino acid motif, which matches the KEAP1 interaction motif found in NRF2.

151 ike ECH-associated protein 1 (KEAP1) via p62-KEAP1 interaction.

152 act that it possesses a novel DLT-containing KEAP1-interaction motif.

153 Keap1 interacts with and promotes the degradation of Ika

154 KEAP1 is a substrate adaptor protein for a CUL3-based E3

155 Because KEAP1 is altered in a number of human pathologies and ha

156 In this study, we show that Keap1 is constantly shuttling between the nucleus and th

157 to electrophiles, the cysteine-rich protein Keap1 is covalently modified, and it is this modificatio

158 As a consequence, free Keap1 is not regenerated, and newly synthesized Nrf2 is

159 KEAP1 is the key regulator of the NRF2-mediated cytoprot

160 KEAP1 is thus poised to affect MCM2-7 dynamics or functi

161 ctual binding orientation and interface with Keap1 is very close to the design model, despite an unex

162 Kelch-like ECH-associated protein 1 (KEAP1) is the main negative regulator of NRF2 and mediat

163 y, NRF1 is more stable in KEAP1(+/+) than in KEAP1(-/-) isogenic cell lines, whereas NRF2 is dramatic

164 Due to increased binding of Nrf2 with Keap1, its translocation to the nucleus is compromised c

165 Lep(ob/ob)-Keap1-KD mice exhibited less lipid accumulation, smaller

166 Next, C57Bl/6J and Keap1-KD mice were fed a high-fat diet (HFD) to determin

167 7Bl/6J, Keap1-KD, Lep(ob/ob), and Lep(ob/ob)-Keap1-KD mice.

168 ion in white adipose tissue was decreased in Keap1-KD mice.

169 Nrf2 activation via Keap1-KD or sulforaphane suppressed hormone-induced diff

170 d type 2 diabetes were measured in C57Bl/6J, Keap1-KD, Lep(ob/ob), and Lep(ob/ob)-Keap1-KD mice.

171 of MARV VP24, driven by its interaction with Keap1 Kelch domain, as a critical determinant that modul

172 agment-based approach to directly target the KEAP1 Kelch-NRF2 interaction.

173 rk of chemoprotective genes regulated by the Keap1 (Kelch-like ECA-associated protein)/Nrf2 (nuclear

174 We found that systemic activation of NRF2 by Keap1 (Kelch-like ECH-associated protein 1) knockdown am

175 rf2 is inhibited by its interaction with the Keap1 (kelch-like ECH-associated protein 1).

176 factor (erythroid-2 related) factor 2 (Nrf2)/Keap1 (Kelch-like ECH-associated protein 1)/ARE (antioxi

177 erythroid 2 [NF-E2]-related factor 2 [Nrf2])-Keap1 (Kelch-like erythroid cell-derived protein with CN

178 Keap1 knockdown led to increased nuclear translocation o

179 ine production were accordingly decreased by Keap1 knockdown.

180 Lep(ob/ob)-Keap1-knockdown (KD) mice, which have increased Nrf2 act

181 we generated skeletal muscle (SkM)-specific Keap1 knockout (Keap1MuKO) mice that express abundant Nr

182 This reduction in Keap1 levels corresponded with Nrf2 nuclear translocatio

183 id, restored miR-200a expression and reduced Keap1 levels.

184 KRAS-driven LUAD, we examined the effects of Keap1 loss in lung cancer progression.

185 NRF2 binds KEAP1 mainly through a conserved "ETGE" motif that has a

186 KEAP1 occur commonly in human cancer, where KEAP1 may function as a tumor suppressor.

187 NRF2 in cancer and provide new insight into KEAP1 mechanics.

188 ed the core amino acid residues required for KEAP1-mediated degradation and further indicated that th

189 uential attachment and regeneration model of Keap1-mediated degradation of Nrf2." This previously una

190 ylation of Cul3, which is essential for Cul3/Keap1-mediated degradation of nuclear factor E2-related

191 NRF2's Neh2 domain renders NRF1 sensitive to KEAP1-mediated degradation, indicating that the amino ac

192 f2 translation by a mechanism independent of Keap1-mediated degradation.

193 ust the motifs themselves, are essential for KEAP1-mediated degradation.

194 duced state of KEAP1, which in turn leads to KEAP1-mediated PGAM5 and Bcl-xL (BCL2L1) degradation.

195 Pre-treatment of Keap1(-/-) MEFs or A549 cells with the LY294002 PI3K inh

196 g, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of the core deregulated p

197 omote mitochondrial turnover, while covalent Keap1 modifiers, including sulforaphane (SFN) and dimeth

198 3'-untranslated region (3'-UTR), leading to Keap1 mRNA degradation.

199 d impair the anchorage-independent growth of KEAP1-mutant cancer cells.

200 NRF2 protein levels and sensitized NFE2L2 or KEAP1-mutant cells to radiation.

201 e proteins that are selectively expressed in KEAP1-mutant NSCLC cells.

202 ex to regulate the transcriptional output of KEAP1-mutant NSCLC cells.

203 ssed at high levels in approximately half of Keap1-mutated lung adenocarcinomas (ADs).

204 ional strategy to treat lung cancer and that KEAP1 mutation status may offer a predicative biomarker

205 To assess whether Nrf2/Keap1 mutations are early or late events in HCC developm

206 In this study, we characterized 18 KEAP1 mutations defined in a lung squamous cell carcinom

207 Our findings identify Keap1 mutations in EOC and they suggest a previously unr

208 We found that Nrf2/Keap1 mutations were present in 71% of early preneoplast

209 discovery of SOX2 amplification, NFE2L2 and KEAP1 mutations, PI3K pathway changes, FGFR1 amplificati

210 y BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together wi

211 s suggest that CDK20 positively modulate the KEAP1-NRF2 cytoprotective pathway to regulate tumor prog

212 igned antibodies bind to Keap1 and block the Keap1-Nrf2 interaction in an epitope-specific way.

213 the therapeutic potential of disrupting the KEAP1-NRF2 interaction.

214 ggest a previously unrecognized role for the Keap1-Nrf2 pathway in mediating chemotherapeutic respons

215 scades activated by nitro-fatty acids is the Keap1-Nrf2 pathway.

216 This study highlights the unique features of Keap1-Nrf2 PPI inhibitors as inducers of mitophagy and t

217 Structurally distinct Keap1-Nrf2 PPI inhibitors promote mitochondrial turnover

218 ll molecules that disrupt the interaction of Keap1-Nrf2.

219 TXNRD1 and AKT pathways occurred through the KEAP1/NRF2 cellular antioxidant pathway.

220 RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to stu

221 udy demonstrates that miR-200a regulates the Keap1/Nrf2 pathway in mammary epithelium, and we find th

222 The Keap1/Nrf2 pathway is a critical regulator of the endoge

223 The Keap1/Nrf2 pathway is a master regulator of antioxidant,

224 observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence

225 the effects of chronic hyperglycemia on the Keap1/Nrf2 pathway within models of diabetic cutaneous w

226 ment and evaluated them as activators of the Keap1/Nrf2/ARE pathway and inhibitors of iNOS.

227 nthesized, and their potency to activate the Keap1/Nrf2/ARE pathway was evaluated.

228 Activation of GSK-3 in Keap1-null mouse embryonic fibroblasts (MEFs), or in hum

229 nse to glucose fluctuations, indicating that KEAP1 O-GlcNAcylation links nutrient sensing to downstre

230 Somatic mutations in KEAP1 occur commonly in human cancer, where KEAP1 may fu

231 Mutations of Keap1 occurred at a much lower frequency in both preneop

232 er by genetic deletion of the NRF2 inhibitor Keap1 or by pharmacological NRF2 activation with 2-trifl

233 ar thiol-driven master switches such as Nrf2/Keap1 or NF-kappaB/IkappaB is used for system-wide oxida

234 Loss of Keap1 or the SWI/SNF complex inhibits generation of DSB

235 man patients with lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung tumors as likely to resp

236 ening and metabolomic analyses, we show that Keap1- or Nrf2-mutant cancers are dependent on increased

237 mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0

238 Recently, dysregulation of the NRF2/KEAP1 pathway and mutations of these genes have been obs

239 Currently, regulation of the Nrf2-Keap1 pathway by ubiquitination is largely understood.

240 In addition, we discovered that the Nrf2/Keap1 pathway detects these compositional changes and di

241 gs further our understanding of how the Nrf2-Keap1 pathway is regulated, which is imperative in targe

242 through silencing of its negative regulator KEAP1 permitted the survival of BRCA1-null cells.

243 Keap1 protein as well as mRNA level decreased concomitan

244 These mutations distribute throughout the KEAP1 protein but little is known about their functional

245 Proteomic analysis of the KEAP1 protein interaction network revealed a significant

246 by selective electrophilic modifications on Keap1 protein, one of several redox-sensitive regulators

247 2,3-triazole compounds that inhibit the Nrf2-Keap1 protein-protein interaction (PPI) in vitro and in

248 merging cancer genes such as MYC, IDH1/2 and KEAP1 regulate tumor metabolism opening up opportunities

249 the pharmacologically induced Nrf2 overcomes Keap1 regulation, translocates to the nucleus, and activ

250 r removal of ubiquitin conjugated to Nrf2 or Keap1 remains unknown.

251 nteraction of mVP24 with Keap1 also relieved Keap1 repression of NF-kappaB reporter activity.

252 mVP24 can relieve Keap1 repression of the NF-kappaB pathway through its in

253 We studied whether mVP24 could relieve Keap1 repression of the NF-kappaB pathway.

254 r a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chem

255 increased p62 binding to the NRF2 inhibitor KEAP1, resulting in reduced proteasomal turnover of NRF2

256 Emerging work points to Nrf2-Keap1 signal transduction pathway inhibitors, including

257 The Nrf2-Keap1 signaling pathway is a protective mechanism promot

258 review provides an overview of (1) the Nrf2-Keap1 signaling pathway, (2) the dual role of Nrf2 in ca

259 F2) and kelch-like ECH-associated protein 1 (KEAP1) signaling promote cellular proliferation and tumo

260 Finally, increased inflammatory responses in Keap1-silenced cells contributed to decreased intracellu

261 e prevented by Nrf2 inducer tBHQ and also by Keap1-siRNA.

262 present evidence that the binding of DPP3 to KEAP1 stabilizes the latter.

263 rimary function of KEAP1; however, few other KEAP1 substrates have been identified.

264 and the related transcription factor NRF1 as KEAP1 substrates.

265 The high frequency of mutations in KEAP1 suggests an important role for the oxidative stres

266 The Nrf2-Keap1 system plays a major role in cellular defense agai

267 Our analysis of a KEAP1 targeting motif in MCM3 suggests that MCM3 is a po

268 Consistently, NRF1 is more stable in KEAP1(+/+) than in KEAP1(-/-) isogenic cell lines, where

269 tly modified, and it is this modification of Keap1 that allows the accumulation and subsequent nuclea

270 protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2.

271 We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcr

272 57, -273, -288, -434, -489, and -613) within Keap1, the major repressor of Nrf2, both in vitro and in

273 mentary manner, Imp-11 functions to restrict KEAP1, the major suppressor of Nrf2, from prematurely ex

274 e cellular ROS sensor and antioxidant factor KEAP1, the phosphatase PGAM5 and the proapoptotic factor

275 e high levels of ROS should have inactivated Keap1, the primary ubiquitin ligase regulating Nrf2 leve

276 e-wide gene knockout approach, we identified Keap1, the SWI/SNF complex, and C9orf82 (CAAP1) as indep

277 rget therein, we sought to better understand KEAP1 through systematic identification of its substrate

278 Four mutations behaved as wild-type KEAP1, thus are likely passenger events.

279 proteins WTX (AMER1), PALB2, and SQSTM1 bind KEAP1 to activate NRF2.

280 Nitroalkenes react with Keap1 to instigate Nrf2 signaling, activate heat shock r

281 main of Kelch-like ECH-associated protein 1 (Keap1) to regulate nuclear factor (erythroid-derived 2)-

282 ic importance of targeting Hrd1, rather than Keap1, to prevent Nrf2 loss and suppress liver cirrhosis

283 Somatic mutations in the KEAP1 ubiquitin ligase or its substrate NRF2 (NFE2L2) co

284 dipeptidyl peptidase 3 (DPP3) protein binds KEAP1 via an "ETGE" motif to displace NRF2, thus inhibit

285 se from Kelch-like ECH-associated protein 1 (KEAP1) via p62-KEAP1 interaction.

286 ar localization of Nrf2 and its binding with Keap1 was investigated in the retina of streptozotocin-i

287 phosphorylated on serine-351 and -403, while Keap1 was polyubiquitinated with lysine-63-ubiquitin cha

288 with normal, whereas Nrf2 protein repressor, Keap1, was unchanged at baseline but increased under oxi

289 p53, and Kelch-like ECH-associated protein1 (Keap1) were investigated using Western blotting and real

290 lforaphane, known ARE activators that target Keap1, were used to validate the assay.

291 ant response, dissociates from its inhibitor Keap1 when activated by stress signals and participates

292 P24 disrupted the interaction of IKKbeta and Keap1, whereas weakly interacting and noninteracting mVP

293 ligase Kelch-like ECH-associated protein 1 (KEAP1), which targets transcriptional factor nuclear fac

294 acts with a second ubiquitin ligase adaptor, KEAP1, which functions to regulate the ubiquitination of

295 ed p62 levels impair interaction of p62 with Keap1, which further decreases Nrf2 function and antioxi

296 TrX-dependent increase in a reduced state of KEAP1, which in turn leads to KEAP1-mediated PGAM5 and B

297 enzyme, USP15, specifically deubiquitinates Keap1, which suppresses the Nrf2 pathway.

298 hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties.

299 ntly to the Nrf2-interacting kelch domain of Keap1 with a Kd of approximately 6 muM, as demonstrated

300 ther, these data establish new functions for KEAP1 within the nucleus and identify MCM3 as a novel su