Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection

Otsuki, Akihito; Suzuki, Mikiko; Katsuoka, Fumiki; Tsuchida, Kouhei; Suda, Hiroko; Morita, Masanobu; Shimizu, Ritsuko; Yamamoto, Masayuki

doi:10.1016/j.freeradbiomed.2015.12.005

Cited by 57 publications

(58 citation statements)

References 60 publications

(53 reference statements)

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“…Several hundred Nrf2 target genes have been identified through gene expression profiling analysis and chromatin immunoprecipitation (ChIP) analysis (12)(13)(14)(15)(16)(17). The Nrf2 target genes identified in these studies include enzymes involved in detoxification, anti-oxidation, and metabolism, as summarized in Fig.…”

Section: Anti-inflammation By Nrf2mentioning

confidence: 99%

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

Suzuki

Yamamoto

2017

Journal of Biological Chemistry

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337

272

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Edited by Ruma BanerjeeTranscription factor Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses the induction of pro-inflammatory cytokine genes. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor subunit of Cullin 3-based E3 ubiquitin ligase. Keap1 regulates the activity of Nrf2 and acts as a sensor for oxidative and electrophilic stresses. In this review, we discuss the molecular mechanisms by which the Keap1-Nrf2 system senses and regulates the cellular response to environmental stresses. In particular, we focus on the multiple stress-sensing mechanisms of Keap1 and novel regulatory functions of Nrf2.Our body is equipped with a defense system that up-regulates the expression levels of cytoprotective enzyme genes. Nrf2 is the central player in the inducible expression of cellular defense enzymes (1, 2). Nrf2 belongs to the CNC (cap-n-collar) subfamily of basic region-leucine zipper-type transcription factors (3). Nrf2 dimerizes with one of the small Maf proteins (sMaf). The Nrf2-sMaf heterodimer binds to the antioxidantresponse element (ARE) 2 or electrophile-response element located in the regulatory regions of many cytoprotective enzyme genes (1, 4 -6). In this way, Nrf2 activates a wide range of cellular defense processes, thereby eliminating harmful substances.Keap1 acts as an E3 ubiquitin ligase substrate-recognition subunit and specifically targets Nrf2 (7-10). In the absence of stress, Nrf2 is efficiently ubiquitinated by the Keap1-Cul3 E3 ligase and degraded rapidly through the proteasome pathway, such that cellular Nrf2 activity is constitutively suppressed. Upon exposure to oxidative or electrophilic stresses, Keap1 loses its ability to ubiquitinate Nrf2, allowing Nrf2 to accumulate in the nucleus and activate its target genes.Recent studies expanded our knowledge on the targets of the Keap1-Nrf2 system, and the molecular mechanisms underpinning how this system senses a variety of environmental stresses. Keap1 primarily regulates Nrf2 in the cytoplasm; however, a Keap1-independent mechanism utilizing ␤-TrCP (␤-transducin repeat-containing protein) in the nucleus also operates (11). Anti-inflammation by Nrf2Several hundred Nrf2 target genes have been identified through gene expression profiling analysis and chromatin immunoprecipitation (ChIP) analysis (12-17). The Nrf2 target genes identified in these studies include enzymes involved in detoxification, anti-oxidation, and metabolism, as summarized in Fig. 1 (18).In addition to protecting against oxidative and xenobiotic insults, Nrf2 has also been known to attenuate inflammation (19). Nrf2 deficiency exacerbates inflammation, such as sepsis, pleurisy, and emphysema, in a variety of murine models (20 -22). In human clinical studies, the Nrf2 inducer Tecfidera (dimethyl fumarate) has been approved for the treatment of multiple sclerosis (23, 24)-at least in part based on its antiinflammatory function. Thus, N...

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Section: Anti-inflammation By Nrf2mentioning

confidence: 99%

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

Suzuki

Yamamoto

2017

Journal of Biological Chemistry

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337

272

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“…More than 10 sensor Cys have been identified in KEAP1, each of which reacts to a variety of electrophiles in different ways to sense many types of oxidative stress [33]. NRF2 molecules that escape from KEAP1-mediated capture and ubiquitination accumulate in the nucleus of cells exposed to oxidative stress and form a heterodimer with small MAF (sMAF) proteins to bind a specific recognition sequence, the CNC-sMAF binding element (CsMBE; 5′-[A/G]TGA[G/C]nnnGC-3′), which is also known as an antioxidant- or electrophile-responsive element [34,35]. Functional CsMBEs are localized in regulatory regions of genes that encode antioxidants, detoxification enzymes, glutathione synthetic enzymes, metabolic enzymes, and heme metabolic enzymes and in genes involved in mitochondrial function (Fig.…”

Section: The Keap1-nrf2 Systemmentioning

confidence: 99%

Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

Nezu¹,

Suzuki

Yamamoto³

2017

Am J Nephrol

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2,553

112

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Background: Nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor for the antioxidative stress response and it activates a variety of cytoprotective genes related to redox and detoxification. NRF2 activity is regulated by the oxidative-stress sensor molecule Kelch-like ECH-associated protein 1 (KEAP1) that induces proteasomal degradation of NRF2 through ubiquitinating NRF2 under unstressed conditions. Because oxidative stress is a major pathogenic and aggravating factor for kidney diseases, the KEAP1-NRF2 system has been proposed to be a therapeutic target for renal protection. Summary: Oxidative-stress molecules, such as reactive oxygen species, accumulate in the kidneys of animal models for acute kidney injury (AKI), in which NRF2 is transiently and slightly activated. Genetic or pharmacological enhancement of NRF2 activity in the renal tubules significantly ameliorates damage related to AKI and prevents AKI progression to chronic kidney disease (CKD) by reducing oxidative stress. These beneficial effects of NRF2 activation highlight the KEAP1-NRF2 system as an important target for kidney disease treatment. However, a phase-3 clinical trial of a KEAP1 inhibitor for patients with stage 4 CKD and type-2 diabetes mellitus (T2DM) was terminated due to the occurrence of cardiovascular events. Because recent basic studies have accumulated positive effects of KEAP1 inhibitors in moderate stages of CKD, phase-2 trials have been restarted. The data from the ongoing projects demonstrate that a KEAP1 inhibitor improves the glomerular filtration rate in patients with stage 3 CKD and T2DM without safety concerns. Key Message: The KEAP1-NRF2 system is one of the most promising therapeutic targets for kidney disease, and KEAP1 inhibitors could be part of critical therapies for kidney disease.

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“…Oxidative and electrophilic stresses inactivate Keap1, thus de novo synthesized Nrf2 translocates into the nucleus where it dimerizes with other transcription factors through its Neh1 domain, in particular with a member of the small musculoaponeurotic fibrosarcoma oncogene homolog (sMAFs) protein family. Indeed, Nrf2 binds DNA only as a heterodimer with sMAFs, thus regulating several genes containing a cis-acting sequence, often present in multiple copies, called ARE (Antioxidant Response Element) or EpRE (Electrophile Response Element) (core ARE/EpRE sequence: 5'-A/GTGAC/GNNNGCA/G-3') [5,7,41,42] discovered in the rat GSTA2 promoter [43]. On the other hand, Nrf2 stability could also be regulated through the phosphorylation of some serine residues in its Neh6 domain by different kinases [7,18,39,41].…”

Section: Nrf2 and Its Regulated Genesmentioning

confidence: 99%

“…Indeed, Nrf2 binds DNA only as a heterodimer with sMAFs, thus regulating several genes containing a cis-acting sequence, often present in multiple copies, called ARE (Antioxidant Response Element) or EpRE (Electrophile Response Element) (core ARE/EpRE sequence: 5'-A/GTGAC/GNNNGCA/G-3') [5,7,41,42] discovered in the rat GSTA2 promoter [43]. On the other hand, Nrf2 stability could also be regulated through the phosphorylation of some serine residues in its Neh6 domain by different kinases [7,18,39,41]. The C-terminal Neh3 domain is involved in transcriptional activation by recruiting the chromo-ATPase/helicase DNA-binding protein (CHD); similarly the Neh4 and Neh5 regions cooperatively interact with CBP (CREB-binding protein)/p300 or BRG1 (Brahma-related gene 1)/SMARCA4 that transactivate Nrf2-dependent transcription.…”

Section: Nrf2 and Its Regulated Genesmentioning

confidence: 99%

See 1 more Smart Citation

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

Paladino

Conte

Caggiano

et al. 2018

Cell Physiol Biochem

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A general hallmark of neurological diseases is the loss of redox homeostasis that triggers oxidative damages to biomolecules compromising neuronal function. Under physiological conditions the steady-state concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are finely regulated for proper cellular functions. Reduced surveillance of endogenous antioxidant defenses and/or increased ROS/RNS production leads to oxidative stress with consequent alteration of physiological processes. Neuronal cells are particularly susceptible to ROS/RNS due to their biochemical composition. Overwhelming evidences indicate that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-linked pathways are involved in protective mechanisms against oxidative stress by regulating antioxidant and phase II detoxifying genes. As such, Nrf2 deregulation has been linked to both aging and pathogenesis of many human chronic diseases, including neurodegenerative ones such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis. Nrf2 activity is tightly regulated by a fine balance between positive and negative modulators. A better understanding of the regulatory mechanisms underlying Nrf2 activity could help to develop novel therapeutic interventions to prevent, slow down or possibly reverse various pathological states. To this end, microRNAs (miRs) are attractive candidates because they are linked to intracellular redox status being regulated and, post-transcriptionally, regulating key components of ROS/RNS pathways, including Nrf2.

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Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection

Cited by 57 publications

References 60 publications

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs

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