Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-TrCP and GSK-3

Hayes, John D.; Chowdhry, Sudhir; Dinkova‐Kostova, Albena T.; Sutherland, Calum

doi:10.1042/bst20150011

Cited by 159 publications

(130 citation statements)

References 106 publications

(97 reference statements)

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“…Nrf2 also engages in cross-talk with several other signalling pathways. Nrf2 regulation at the protein level occurs by the ubiquitin proteasome system [1,2]. The ability of Keap1 to direct Nrf2 ubiquitylation by the Cul3 (cullin-3)-Rbx1 (ring-box protein 1) E3 ubiquitin ligase and subsequent proteasomal degradation is well documented and a cycling mechanism by which Keap1 interacts with Nrf2 and only releases the protein once the transcription factor is ubiquitylated has been identified [1].…”

Section: Nrf2 Regulationmentioning

confidence: 99%

“…Nrf2 activity can be increased by exposure to soft electrophiles, phytochemicals, oxidants, growth factors, drugs, toxins and numerous other stimuli [2]. Due to its broad effects and wide range of agonists, Nrf2 activation is tightly controlled at multiple levels.…”

Section: Nrf2 Regulationmentioning

confidence: 99%

“…It regulates directly approximately 250 genes that are involved in cell homoeostasis, including those for antioxidant proteins, detoxification enzymes, drug transporters and numerous cytoprotective proteins, and it also influences energy metabolism, inflammation and cell growth [1][2][3]. Studies using Nrf2 knockout mice and small molecule activators, usually called inducers, have demonstrated beneficial effects in several animal models of chronic age-related and inflammatory diseases [1,[3][4][5].…”

Section: Introductionmentioning

confidence: 99%

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The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic

O’Connell

Hayes

2015

Biochemical Society Transactions

Self Cite

143

109

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The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, with gene called NFE2L2) is a master regulator of the antioxidant response. In the last decade, interest has intensified in this research area as its importance in several physiological and pathological processes has become widely recognized; these include redox signalling and redox homoeostasis, drug metabolism and disposition, intermediary metabolism, cellular adaptation to stress, chemoprevention and chemoresistance, toxicity, inflammation, neurodegeneration, lipogenesis and aging. Regulation of Nrf2 is complex and although much attention has focussed on its repression by Kelch-like ECH-associated protein-1 (Keap1), recently it has become increasingly apparent that it is also controlled by cross-talk with other signalling pathways including the glycogen synthase kinase-3 (GSK-3)-β-transducin repeat-containing protein (β-TrCP) axis, ERAD (endoplasmic reticulum-associated degradation)-associated E3 ubiquitin-protein ligase (Hrd1, also called synoviolin), nuclear factor-kappa B (NF-κB), Notch and AMP kinase. Due to its beneficial role in several diseases, Nrf2 has become a major therapeutic target, with novel natural, synthetic and targeted small molecules currently under investigation to modulate the pathway and in clinical trials.

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Section: Nrf2 Regulationmentioning

confidence: 99%

Section: Nrf2 Regulationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic

O’Connell

Hayes

2015

Biochemical Society Transactions

Self Cite

143

109

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“…Thus, inactivation of Keap1 allows Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry newly synthesized Nrf2 to translocate into the nucleus [7,8,39,50]. Nrf2 stabilization is also regulated by SCF/β-TrCP complex, involving the S-phase kinase-associated protein 1 (Skp1), Cullin-1 (Cul1) and F-box protein E3 ubiquitin ligase [39,51]. This regulation is unrelated to redox-sensitive modifications via reactive cysteine residues of Keap1.…”

Section: Negative Regulatorsmentioning

confidence: 99%

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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“…β-TrCP leads to Cullin-1/Rbx1-mediated NRF2 ubiquitination and its subsequent degradation [48]. It has been described that phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB)/AKT signaling results inhibitory phosphorylation of GSK3, preventing the formation of a DSGIS motif-containing phosphodegron in NRF2 that is recognized by the β-TrCP [48,49].…”

Section: The Transcription Factor Nrf2mentioning

confidence: 99%

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

Lastres‐Becker¹

2017

J Alzheimers Dis Parkinsonism

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Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-TrCP and GSK-3

Cited by 159 publications

References 106 publications

The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic

The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic

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

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

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