Mus musculus
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-71695
PROVIDER: PRJNA291845 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Characterization of RA839, a non-covalent small-molecule binder to Keap1 and selective activator of Nrf2 signalling
2016-01-08 | E-GEOD-71695 | ExpressionAtlas
Project description:The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors the activity of Nrf2 is inhibited by its interaction with the kelch-like ECH-associated protein 1 (Keap1). Here, we describe RA839, a small molecule that binds non-covalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of approximately 6 µM, as demonstrated by X-ray co-crystallization and isothermal titration calorimetry. Whole-genome DNA arrays showed that at 10 µM RA839 significantly regulated 105 genes in bone marrow-derived macrophages. Canonical pathway mapping of these genes revealed an activation of pathways linked with Nrf2 signalling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knockout macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound CDDO-Me, RA839 prevented the induction of both inducible nitric oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice RA839 acutely induced Nrf2-target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2. Gene expression profile of bone marrow derived murine macrophages (BMDM) from Nrf2+/+ or Nrf2-/- mice treated with RA838, siKeap1-1 or siKeap1-2 were compared to untreated DMSO control or siControl. Four biological replicates were used for each sample group.
2015-10-31 | E-GEOD-71695 | biostudies-arrayexpress
Project description:The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors the activity of Nrf2 is inhibited by its interaction with the kelch-like ECH-associated protein 1 (Keap1). Here, we describe RA839, a small molecule that binds non-covalently to the Nrf2-interacting kelch domain of Keap1 with a Kd of approximately 6 µM, as demonstrated by X-ray co-crystallization and isothermal titration calorimetry. Whole-genome DNA arrays showed that at 10 µM RA839 significantly regulated 105 genes in bone marrow-derived macrophages. Canonical pathway mapping of these genes revealed an activation of pathways linked with Nrf2 signalling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knockout macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound CDDO-Me, RA839 prevented the induction of both inducible nitric oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice RA839 acutely induced Nrf2-target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2.
2015-10-31 | GSE71695 | GEO
Project description:Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct hepatic gene expression profiles between Keap1 knockout and triterpenoid treated mice; Loss of Nrf2 signaling increases susceptibility to acute toxicity, inflammation, and carcinogenesis in mice due to the inability to mount adaptive responses. By contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice; although dominant negative mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. This analysis also enables a global characterization of the pharmacodynamic action of CDDO-Im at a low dose that is relevant to chemoprevention. Experiment Overall Design: Liver-targeted conditional Keap1-null (CKO) mice provide a model of genetic activation of Nrf2 signaling. By coupling global gene expression analysis of CKO mice with analysis of pharmacologic activation using the synthetic oleanane triterpenoid CDDO-Im, we are able to gain insight into pathways affected by Nrf2 activation. CDDO-Im is an extremely potent activator of Nrf2 signaling. CKO mice were used to identify genes modulated by genetic activation of Nrf2 signaling. The CKO response was compared to hepatic global gene expression changes in wild-type mice treated with CDDO-Im at a maximal Nrf2 activating dose. n=3/group, male 9 week old mice were used. Mice were treated with a single dose of vehicle (10% Cremophor-EL, 10% DMSO, and PBS) or 30 umol CDDO-Im/kg body weight by gavage and sacrificed 6 h later.
2009-05-11 | E-GEOD-15633 | biostudies-arrayexpress
Project description:Constitutive activation of NRF2 provides a selective advantage to malignant tumour clones through the hijacking of the NRF2-dependent cytoprotective transcriptional program, which allows the cancer cells to survive and thrive in the chemically stressful tumour niche, whilst also providing resistance to anti-cancer drugs due to the upregulation of xenobiotic metabolizing enzymes and drug efflux pumps. Through a small-molecule epigenetic screen carried out in KEAP1 mutant lung cancer cells, in this study, we identified CCS1477 (Inobrodib) to be an inhibitor of the global NRF2-dependent transcription program. Mechanistically, CCS1477 is able to repress NRF2’s cytoprotective response through the inhibition of its obligate transcriptional activator partner CBP/ p300. Importantly, in addition to repressing NRF2-dependent anti-oxidative stress and xenobiotic metabolizing enzyme gene expression, CCS1477 treatment is also able to reverse the chemoresistance phenotype and re-sensitize NRF2-activated tumour cells to anti-cancer drugs. Furthermore, in co-culture experiments of KEAP1 mutant cancer cells with primary human T cells, CCS1477 treatment suppressed the acquisition of the T cell exhaustion transcriptional state, which should function to augment the anti-cancer immune response. Thus, CCS1477-mediated inhibition of CBP/ p300 represents a novel therapeutic strategy with which to target the currently untreatable tumours with aberrant NRF2 activation.
2025-03-31 | GSE292969 | GEO
Project description:The transcription factor NF-E2-related factor 2 (Nrf2) induces cytoprotective genes, but has also been linked to the regulation of hepatic energy metabolism. In order to assess the pharmacological potential of hepatic Nrf2 activation in metabolic disease, Nrf2 was activated over 8 weeks in mice on Western diet using two different siRNAs against kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2. Whole genome expression analysis followed by pathway analysis demonstrated that the suppression of Keap1 expression induced genes that are involved in anti-oxidative stress defense and biotransformation, pathways proving the activation of Nrf2 by the siRNAs against Keap1. The expression of neither fatty acid- nor carbohydrate-handling proteins was regulated by the suppression of Keap1. Metabolic profiling of the animals did also not show effects on plasma and hepatic lipids, energy expenditure or glucose tolerance by the activation of Nrf2. The data indicate that hepatic Nrf2 is not a major regulator of intermediary metabolism in mice. Gene expression profile of mouse liver samples from 8-week-old male C57BL6/J mice (N=24) treated with liver-selective Keap1-specific siRNA (group 1: siKeap1-1, N=8; group 2: siKeap1-2, N=8) or unspecific scrambled control siRNA (group 3: siControl, N=8)
2016-09-01 | E-GEOD-80956 | biostudies-arrayexpress
Project description:Novel KEAP1 activator targeting C151 enhances CUL3 binding and decreases NRF2
2025-12-10 | PXD056257 | Pride
Project description:One of the major metabolic responses to counteract aging, inflammation, and various chronic diseases including neurodegeneration, is the so call antioxidant pathway controlled by Nrf2 transcription factor. Nrf2 protein stability is regulated via interaction with the redox sensor Keap1, an adapter protein in Cullin III ubiquitin ligase complex. The search for Nrf2 activators is mainly focused on compounds that either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered as the most appropriate one for continuous administration without side effects, which are unavoidable in case of non-specific chemical modifiers of Keap1. However, true displacement activators show a significant offset, by many orders of magnitude, when switched from homogeneous assay to cell-based assays. This phenomenon originates, as we show here, from high micromolar intracellular concentrations of Keap1. A guarantee for high specificity of an alkylating Nrf2 activator is its targeted delivery. A transcriptomic analysis for a cell-permeable Nrf2-peptide bearing a fumarate moiety shows the activation of the antioxidant program only, confirming the high specificity of such approach. However, aging-linked neurodegeneration is also known to build-up Bach1, an Nrf2 target gene and competitive transcriptional repressor for Nrf2. Therefore, an ideal combination could be a benign Nrf2 activator and Bach1 inhibitor in one molecule, as represented by the recently developed HPPE. HPPE demonstrates an intersection of the activated antioxidant pathway with the Nrf2 peptide, and, in addition to that, shows a big pool of genes overlapping with the known inhibitors of Bach1 - zinc and tin protoporphyrins. Hence, at present moment, HPPE presents a unique combination of the two desired activities beneficial for age-related neurodegeneration.
2025-08-20 | GSE271364 | GEO
Project description:One of the major metabolic responses to counteract aging, inflammation, and various chronic diseases including neurodegeneration, is the so call antioxidant pathway controlled by Nrf2 transcription factor. Nrf2 protein stability is regulated via interaction with the redox sensor Keap1, an adapter protein in Cullin III ubiquitin ligase complex. The search for Nrf2 activators is mainly focused on compounds that either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered as the most appropriate one for continuous administration without side effects, which are unavoidable in case of non-specific chemical modifiers of Keap1. However, true displacement activators show a significant offset, by many orders of magnitude, when switched from homogeneous assay to cell-based assays. This phenomenon originates, as we show here, from high micromolar intracellular concentrations of Keap1. A guarantee for high specificity of an alkylating Nrf2 activator is its targeted delivery. A transcriptomic analysis for a cell-permeable Nrf2-peptide bearing a fumarate moiety shows the activation of the antioxidant program only, confirming the high specificity of such approach. However, aging-linked neurodegeneration is also known to build-up Bach1, an Nrf2 target gene and competitive transcriptional repressor for Nrf2. Therefore, an ideal combination could be a benign Nrf2 activator and Bach1 inhibitor in one molecule, as represented by the recently developed HPPE. HPPE demonstrates an intersection of the activated antioxidant pathway with the Nrf2 peptide, and, in addition to that, shows a big pool of genes overlapping with the known inhibitors of Bach1 - zinc and tin protoporphyrins. Hence, at present moment, HPPE presents a unique combination of the two desired activities beneficial for age-related neurodegeneration.
2025-08-20 | GSE287793 | GEO
Project description:Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct hepatic gene expression profiles between Keap1 knockout and triterpenoid treated mice Loss of Nrf2 signaling increases susceptibility to acute toxicity, inflammation, and carcinogenesis in mice due to the inability to mount adaptive responses. By contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice; although dominant negative mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. This analysis also enables a global characterization of the pharmacodynamic action of CDDO-Im at a low dose that is relevant to chemoprevention.
2009-05-01 | GSE15633 | GEO