KEAP1, a cysteine-based sensor and a drug target for the prevention and treatment of chronic disease

Naidu, Sharadha Dayalan; Dinkova‐Kostova, Albena T.

doi:10.1098/rsob.200105

Cited by 83 publications

(62 citation statements)

References 145 publications

(290 reference statements)

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“…There is the potential that SF-3-030 forms a covalent adduct with Kelch-like ECH-associated protein 1 (KEAP1), the negative regulator of NRF2. KEAP1 has up to 21 cysteine residues that may be modified by chemical stressors to relieve KEAP1 inhibition and allow NRF2 activation ( Dayalan Naidu and Dinkova-Kostova, 2020 ). Sulforaphane, which modifies KEAP1 on C151 to activate NRF2, showed qualitative differences in the expression of NRF2-regulated genes as compared with SF-3-030 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Analysis of an Extracellular Signal–Regulated Kinase 2–Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress

Martínez

Huang

Samadani

et al. 2020

J Pharmacol Exp Ther

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Constitutively active extracellular signal–regulated kinase (ERK) 1/2 signaling promotes cancer cell proliferation and survival. We previously described a class of compounds containing a 1,1-dioxido-2,5-dihydrothiophen-3-yl 4-benzenesulfonate scaffold that targeted ERK2 substrate docking sites and selectively inhibited ERK1/2-dependent functions, including activator protein-1–mediated transcription and growth of cancer cells containing active ERK1/2 due to mutations in Ras G-proteins or BRAF, Proto-oncogene B-RAF (Rapidly Acclerated Fibrosarcoma) kinase. The current study identified chemical features required for biologic activity and global effects on gene and protein levels in A375 melanoma cells containing mutant BRAF (V600E). Saturation transfer difference-NMR and mass spectrometry analyses revealed interactions between a lead compound ( SF-3-030 ) and ERK2, including the formation of a covalent adduct on cysteine 252 that is located near the docking site for ERK/FXF (DEF) motif for substrate recruitment. Cells treated with SF-3-030 showed rapid changes in immediate early gene levels, including DEF motif–containing ERK1/2 substrates in the Fos family. Analysis of transcriptome and proteome changes showed that the SF-3-030 effects overlapped with ATP-competitive or catalytic site inhibitors of MAPK/ERK Kinase 1/2 (MEK1/2) or ERK1/2. Like other ERK1/2 pathway inhibitors, SF-3-030 induced reactive oxygen species (ROS) and genes associated with oxidative stress, including nuclear factor erythroid 2–related factor 2 (NRF2). Whereas the addition of the ROS inhibitor N -acetyl cysteine reversed SF-3-030 –induced ROS and inhibition of A375 cell proliferation, the addition of NRF2 inhibitors has little effect on cell proliferation. These studies provide mechanistic information on a novel chemical scaffold that selectively regulates ERK1/2-targeted transcription factors and inhibits the proliferation of A375 melanoma cells through a ROS-dependent mechanism. SIGNIFICANCE STATEMENT Constitutive activation of the extracellular signal–regulated kinase (ERK1/2) pathway drives the proliferation and survival of many cancer cell types. Given the diversity of cellular functions regulated by ERK1/2, the current studies have examined the mechanism of a novel chemical scaffold that targets ERK2 near a substrate binding site and inhibits select ERK functions. Using transcriptomic and proteomic analyses, we provide a mechanistic basis for how this class of compounds inhibits melanoma cells containing mutated BRAF and active ERK1/2.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Analysis of an Extracellular Signal–Regulated Kinase 2–Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress

Martínez

Huang

Samadani

et al. 2020

J Pharmacol Exp Ther

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“…Phase 2 inducers are agents that trigger the increased expression of a wide range of antioxidant, detoxifying, and cytoprotective enzymes [ 58 ]. Many of them accomplish this by interacting covalently with cysteine groups of Keap1, a protein that binds to the transcription factor nrf2, retaining it in the cytoplasm and promoting its proteasomal degradation [ 59 , 60 ]. When phase 2 inducers—or their electrophilic metabolites—bind to Keap1, nrf2 is freed up to migrate to the nucleus and promote the transcription of many cytoprotective enzymes, the promoters of whose genes contain antioxidant response elements capable of binding nrf2.…”

Section: Nlrp3 Inflammasome Suppression Via Phase 2 Inductionmentioning

confidence: 99%

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

et al. 2020

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Inflammasomes are intracellular protein complexes that form in response to a variety of stress signals and that serve to catalyze the proteolytic conversion of pro-interleukin-1β and pro-interleukin-18 to active interleukin-1β and interleukin-18, central mediators of the inflammatory response; inflammasomes can also promote a type of cell death known as pyroptosis. The NLRP3 inflammasome has received the most study and plays an important pathogenic role in a vast range of pathologies associated with inflammation—including atherosclerosis, myocardial infarction, the complications of diabetes, neurological and autoimmune disorders, dry macular degeneration, gout, and the cytokine storm phase of COVID-19. A consideration of the molecular biology underlying inflammasome priming and activation enables the prediction that a range of nutraceuticals may have clinical potential for suppressing inflammasome activity—antioxidants including phycocyanobilin, phase 2 inducers, melatonin, and N-acetylcysteine, the AMPK activator berberine, glucosamine, zinc, and various nutraceuticals that support generation of hydrogen sulfide. Complex nutraceuticals or functional foods featuring a number of these agents may find utility in the prevention and control of a wide range of medical disorders.

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“…The classic mechanism of NRF2 activation is in response to electrophilic insults in the cell [ 39 ]. Under non-stressed conditions, KEAP1-mediated NRF2 degradation limits the amount of NRF2 available to translocate to the nucleus to induce target gene expression [ 2 ]. Under stressed conditions (i.e., high ROS levels), KEAP1-mediated degradation of NRF2 is inhibited, and NRF2 accumulates in the nucleus where it can promote transcription of ARE-containing genes involved in oxidative damage prevention and redox homeostasis [ 38 ].…”

Section: Metabolic Pathways That Stabilize Nrf2mentioning

confidence: 99%

“…Further, it was determined that C273 and C288 in KEAP1’s linker domain are required for KEAP1-mediated repression of NRF2 [ 101 ]. Importantly, many diseases cause oxidative stress that can result in modification of KEAP1 cysteine residues and prompt NRF2 activation, including cancer, diabetes, neurogenerative disease, and inflammation-related diseases, among others [ 2 ]. Overall, the KEAP1-NRF2 axis facilitates redox homeostasis and cytoprotection.…”

Section: Metabolic Pathways That Stabilize Nrf2mentioning

confidence: 99%

“…NRF2 directs the transcription of both the antioxidant program and metabolic processes that support its function. NRF2 levels are controlled by its interaction with KEAP1, a substrate adaptor for a cullin 3 (CUL3)-based E3 ubiquitin ligase that targets NRF2 for ubiquitination and proteasomal degradation [ 2 ], as highlighted in Figure 1 . While NRF2 protein levels are highly inducible in normal cells in response to oxidative and xenobiotic stress or electrophile exposure, constitutive NRF2 expression is observed in several cancers [ 3 , 4 , 5 , 6 , 7 , 8 ], including the squamous and adenocarcinoma subtypes of non-small cell lung cancer (NSCLC) [ 3 ], and squamous cancers of the esophagus, skin, larynx, and other tissues [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

DeBlasi

DeNicola

2020

Cancers

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The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes.

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KEAP1, a cysteine-based sensor and a drug target for the prevention and treatment of chronic disease

Cited by 83 publications

References 145 publications

Mechanistic Analysis of an Extracellular Signal–Regulated Kinase 2–Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress

Mechanistic Analysis of an Extracellular Signal–Regulated Kinase 2–Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

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