ライフサイエンスコーパス: Keap1

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

2 e S-transferase pi (GSTP), serum albumin, or Keap1.

3 ction between endogenous DPP3 and endogenous KEAP1.

4 nstance, mutations in the negative regulator KEAP1.

5 ved in the degradation of the Nrf2 inhibitor Keap1.

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

7 nd mutants of mVP24 defective for binding to Keap1.

8 -kappaB pathway through its interaction with Keap1.

9 1 enhanced IKKbeta levels in the presence of Keap1.

10 limiting the repressive activity of nuclear KEAP1.

11 reacting with thiols on the adaptor protein, Keap1.

12 e pronounced in cell lines expressing mutant KEAP1.

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

14 sion of Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2, and second, Sirt6

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

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

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

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

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

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

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

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

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

24 glutathione pathways and harbor more NFE2L2/KEAP1 alterations and copy gain in the 3q2 locus.

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

26 OS, we found irregular inhibition of Nrf2 by Keap1, altered metabolism, and limited BMSC multipotency

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

28 crucial for cytoprotective response, whereas Keap1-an endogenous inhibitor of Nrf2 signaling-dampens

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

30 s in LncRNA MALAT1 and its interactions with Keap1 and decreases in Nrf2-mediated antioxidant defense

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

32 siRNA prevented glucose-induced increase in Keap1 and facilitated Nrf2 nuclear translocation and ant

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

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

35 hilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are no

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

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

38 Mutations in KEAP1 and NFE2L2 (encoding the protein Nrf2) are prevale

39 his feature disrupts the interaction between Keap1 and Nrf2.

40 ilarly show increased cytoplasmic binding of KEAP1 and RBM45.

41 This effect promotes p62 recruitment of Keap1 and subsequent Nrf2-mediated stress response.

42 n based on the structure of its complex with Keap1 and synthetic access.

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

44 lidated known and novel interactions between KEAP1 and the proteins PGAM5 and HK2, among others, unde

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

46 114 nM) and disrupts the interaction between KEAP1 and the transcription factor NRF2.

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

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

49 orylate kelch like ECH associated protein 1 (Keap1) and prevent Keap1 polymerization, thereby blockin

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

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

52 , are necessary for interactions with PGAM5, KEAP1, and other regulators of the antioxidant response,

53 xpression of HO-1, reduced the expression of Keap1, and promoted Nrf2 into the nuclear in LPS-stimula

54 2 is mediated by its intracellular inhibitor Keap1, and retinal Keap1 levels are increased in diabete

55 ulator of NRF2, KEAP1 Of these, ATG12, ATG7, KEAP1, and VPS37A are known to be involved in autophagic

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

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

58 adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabo

59 Our study establishes Nrf2/Keap1 as a cytoprotective pathway, as well as a metaboli

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

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

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

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

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

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

66 in and host protein Keap1, MLAV VP24 lacks a Keap1-binding motif and fails to activate this cytoprote

67 lement reporter gene due to the absence of a Keap1-binding motif.

68 Here, we demonstrated that GULP1 was a KEAP1-binding protein that maintained actin cytoskeleton

69 er, our findings demonstrate that GULP1 is a KEAP1-binding protein that regulates KEAP1-NRF2 signalin

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

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

72 on with Kelch-like ECH-associated protein 1 (Keap1), but REDD1-mediated Nrf2 degradation required gly

73 er, we show that CDDO-Im binds covalently to Keap1 by forming permanent Michael adducts with eight di

74 P1S accelerates p62-dependent degradation of KEAP1 by the autophagy pathway.

75 Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation.

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

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

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

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

80 uggest that the Tyr 85 adduct stabilizes the Keap1-Cul3 complex, thereby enhancing the potency of CDD

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

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

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

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

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

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

87 58%, P = 0.03) were significantly reduced by Keap1 deficiency in male mice.

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

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

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

91 of Nrf2 in skeletal muscle following Nrf2 or Keap1 deletion.

92 l conditions and an induced effect through a Keap1-dependent mechanism in response to oxidative and o

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

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

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

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

97 Deletion or knockdown of Keap1 enhanced the gene expression of Nrf2, ALP and wnt5

98 ted with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenog

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

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

101 Both wildtype and Keap1(f/f) pups at PND1 were exposed to hyperoxia for 72

102 hypoalveolarization was remarkably lower in Keap1(f/f) pups than in wildtype counterparts (28.9% vs

103 Lack of hypoalveolarization in Keap1(f/f) pups was accompanied by increased levels of e

104 Likewise, Keap1(f/f) pups were protected against prolonged (96 h)

105 ng bearing hypomorphic Keap1 floxed alleles (Keap1(f/f)) with increased levels of Nrf2 to test the hy

106 ype counterparts (28.9% vs 2.4%, wildtype vs Keap1(f/f)).

107 , and RNA sequencing), its interactions with Keap1 (FACS), Keap1-Nrf2 interactions, and transcription

108 ouse models; the iMS-Nrf2(flox/flox) and iMS-Keap1(flox/flox) , employing which we demonstrated that

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

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

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

112 -1 hairless mice in which Nrf2 is disrupted (Keap1(flox/flox)/Nrf2(-/-)) and subjected them chronical

113 e used PND1 pups bearing bearing hypomorphic Keap1 floxed alleles (Keap1(f/f)) with increased levels

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

115 es with Kelch-like ECH-associated protein 1 (KEAP1) for NRF2 binding through an ETGE motif, and (2) M

116 ping for the redox regulated sensor protein, KEAP1, for the first time in live cells.

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

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

119 iption factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxid

120 We examined bone phenotype of Keap1 heterozygotic mice (Ht) in comparison with Keap1 w

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

122 th their age-matched littermate WT controls, Keap1 Ht mice showed significant increase in bone format

123 T mice, serum bone resorption marker in male Keap1 Ht mice was significantly decreased.

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

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

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

127 if moderate Nrf2 activation by disruption of Keap1 impacts bone metabolism.

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

129 at moderate Nrf2 activation by disruption of Keap1 improved bone mass by regulating bone remodeling i

130 epatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo.

131 tand Nrf2 function: a tonic effect through a Keap1-independent mechanism under basal conditions and a

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

133 Keap1 inhibition increased Nrf2 nuclear translocation, i

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

135 or starting points for developing CNS-active Keap1 inhibitors.

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

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

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

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

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

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

142 Keap1 interacts with and promotes the degradation of Ika

143 Keap1 is a negative controller of the transcription fact

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

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

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

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

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

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

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

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

152 disrupting the interaction of NRF2 with the KEAP1 Kelch domain.

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

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

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

156 raction of NRF2 with its negative regulator, KEAP1 (Kelch-like ECH-associated protein 1).

157 Keap1 knockdown led to increased nuclear translocation o

158 Keap1 knockdown resulted in upregulation of lung cell pr

159 ine production were accordingly decreased by Keap1 knockdown.

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

161 sidered as the basal function of Nrf2, while Keap1 KO-changed proteins are involved in cellular detox

162 Canonical pathway analysis suggested that Keap1-KO activated four pathways, whereas Nrf2-KO did no

163 -KO changed expression of 114 proteins while Keap1-KO changed expression of 117 proteins with 10 prot

164 y analysis further revealed that Nrf2-KO and Keap1-KO impacted different signal proteins and function

165 ancestor disrupted the repression of NRF2 by KEAP1, leading to constitutive NRF2 activity and decreas

166 s intracellular inhibitor Keap1, and retinal Keap1 levels are increased in diabetes.

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

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

169 ting endogenous Nrf2 activation by targeting Keap1 may provide a physiological way to prevent hypoalv

170 ed by a surge of Nrf2 that is dependent on a Keap1 mechanism.

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

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

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

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

175 hyperactivation of Nrf2 causes osteopenia in Keap1(-/-) mice, and Keap1(-/-) osteoblasts have signifi

176 on between its VP24 protein and host protein Keap1, MLAV VP24 lacks a Keap1-binding motif and fails t

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

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

179 gh intracellular cysteine, particularly NRF2/KEAP1 mutant cells.

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

181 thways critical for Nrf2-dependent growth in KEAP1-mutant cell lines, including the redox proteins th

182 IGF1R inhibition was effective in KEAP1-mutant cells compared with WT, especially under co

183 for the proliferation and tumorigenicity of KEAP1-mutant non-small cell lung cancer.

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

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

186 These results point to addiction of KEAP1-mutant tumor cells to Nrf2 and suggest that inhibi

187 ed almost complete regression of established KEAP1-mutant tumors in mice, with little effect on wild-

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

189 We demonstrate that a KEAP1 mutation in the Neoavian ancestor disrupted the re

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

191 total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53

192 dition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC.

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

194 by a bifunctional small molecule linking the KEAP1-Nrf2 activator bardoxolone to a BRD4 inhibitor JQ1

195 ts the TRIM21 function to upregulate the p62-Keap1-Nrf2 antioxidant pathway for efficient viral patho

196 data suggest that the activation of the p62-Keap1-Nrf2 antioxidant response induced by the NSs-TRIM2

197 E3 ligase plays an essential role in the p62-Keap1-Nrf2 axis pathway for redox homeostasis.

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

199 study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological

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

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

202 encing), its interactions with Keap1 (FACS), Keap1-Nrf2 interactions, and transcription of the antiox

203 ertheless, the physicochemical nature of the KEAP1-NRF2 interface suggests that achieving high affini

204 Disruption of the KEAP1-NRF2 pathway results in the transactivation of NRF

205 electrophile sensor of mammalian cells, the KEAP1-NRF2 pathway, to discover cysteine-reactive electr

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

207 oncogenic pathways in PrSPCs, including the KEAP1-NRF2 pathway.

208 irst side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence pola

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

210 Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, bu

211 Structurally distinct Keap1-Nrf2 PPI inhibitors promote mitochondrial turnover

212 activation through direct modulation of the KEAP1-NRF2 protein-protein interaction is being increasi

213 of an uncharged macrocyclic inhibitor of the Keap1-Nrf2 protein-protein interaction, a particularly c

214 P1 is a KEAP1-binding protein that regulates KEAP1-NRF2 signaling in UCB and that promoter hypermethy

215 fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes en

216 Thus, LncRNA MALAT1, via Keap1-Nrf2, regulates antioxidant defense in diabetic re

217 e role of LncRNA MALAT1 in the regulation of Keap1-Nrf2-antioxidant defense in diabetic retinopathy.

218 ration activity and negatively regulates the Keap1-Nrf2-mediated antioxidant response.

219 The KEAP1-NRF2-mediated cytoprotective response plays a key

220 egnant rats, an effect related to changes in Keap1/Nrf2 and nuclear factor-kappaB signalling.

221 disturbed superoxide dismutase 1 (SOD1) and Keap1/Nrf2 antioxidant responses constitute important co

222 nction, disturbed superoxide dismutase 1 and Keap1/Nrf2 antioxidant responses, over-production of rea

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

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

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

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

227 sis that dysregulation of the cell cycle and Keap1/Nrf2 pathway play a role in initiating the kidney

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

229 ts IkappaB/NF-kappaB signaling, and enhances Keap1/Nrf2 signaling in mice with UUO or ischemia/reperf

230 The Keap1/Nrf2 signaling pathway has been considered as a ma

231 organ function including the cell cycle, and Keap1/Nrf2 signaling.

232 ccumulation and activation of CUL3 substrate Keap1/Nrf2, proposed to be protective in kidney injury.

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

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

235 ell as Kelch-like ECH-associating protein 1 (Keap1), nuclear factor erythroid 2 related factor 2 (Nrf

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

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

238 d the well-known negative regulator of NRF2, KEAP1 Of these, ATG12, ATG7, KEAP1, and VPS37A are known

239 MARV VP24 in that it failed to interact with Keap1 or activate an antioxidant response element report

240 In mouse models of lung cancers, loss of Keap1 or Fbxo22 induces metastasis in a Bach1-dependent

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

242 man lung cancers acquire mutations in either Keap1 or Nfe2l2, resulting in the stabilization of Nrf2,

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

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

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

246 nificantly less proliferative potential than Keap1(+/-) osteoblasts.

247 f2 causes osteopenia in Keap1(-/-) mice, and Keap1(-/-) osteoblasts have significantly less prolifera

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

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

250 kelch-like erythroid cell-derived protein 1 (Keap1) pathway is dysregulated and functionally insuffic

251 ECH associated protein 1 (Keap1) and prevent Keap1 polymerization, thereby blocking Nrf2 ubiquitinati

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

253 2,3-triazole compounds that inhibit the Nrf2-Keap1 protein-protein interaction (PPI) in vitro and in

254 r KREPs including that of the cancer-related KEAP1 protein.

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

256 eceptor subunits GluN1 and GluN2A as well as KEAP1 (regulator of transcription factor NRF2).

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

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

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

260 directed transcription, through knockdown of Keap1, restores redox homeostasis.

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

262 elective deletion of skeletal muscle Nrf2 or Keap1 separately impaired or improved skeletal muscle fu

263 This facilitated p62-mediated Keap1 sequestration and ultimately increased Nrf2-mediat

264 ing metabolic or redox stress confirmed that KEAP1 sheds many basal interactions and becomes associat

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

266 Normalized Nrf2/Keap1 signaling restores multipotent cell properties in

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

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

269 tions in the airway field (e.g., TP53, KRAS, KEAP1, STK11, and CDKN2A) and those with single hits pro

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

271 and the related transcription factor NRF1 as KEAP1 substrates.

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

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

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

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

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

277 57, -273, -288, -434, -489, and -613) within Keap1, the major repressor of Nrf2, both in vitro and in

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

279 lung cancers (NSCLC) harboring mutations in KEAP1, the negative regulator of NRF2.

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

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

282 to Nrf2 and antagonizes its interaction with Keap1, thereby stabilizing Nrf2 levels in cardiomyocytes

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

284 d actin cytoskeleton architecture and helped KEAP1 to sequester NRF2 in the cytoplasm.

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

286 n mice, with little effect on wild-type (WT) KEAP1 tumors.

287 tor 2 (Nrf2) dissociates from its inhibitor, Keap1, upon stress signals and subsequently induces an a

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

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

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

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

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

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

294 ning was decreased in patient corneas, while KEAP1, which helps to degrade NRF2, was increased.

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

296 1 heterozygotic mice (Ht) in comparison with Keap1 wild type (WT) mice.

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

298 One of the lead inhibitors (iKeap1) engages KEAP1 with nanomolar affinity (dissociation constant (K(

299 structurally diverse molecules that bind to KEAP1 with submicromolar affinity.

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