title: Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-TrCP and GSK-3.
abstract: Nuclear factor-erythroid 2 p45 (NF-E2 p45)-related factor 2 (Nrf2) is a master regulator of redox homoeostasis that allows cells to adapt to oxidative stress and also promotes cell proliferation. In this review, we describe the molecular mechanisms by which oxidants/electrophilic agents and growth factors increase Nrf2 activity. In the former case, oxidants/electrophiles increase the stability of Nrf2 by antagonizing the ability of Kelch-like ECH-associated protein 1 (Keap1) to target the transcription factor for proteasomal degradation via the cullin-3 (Cul3)-RING ubiquitin ligase CRL(Keap1). In the latter case, we speculate that growth factors increase the stability of Nrf2 by stimulating phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB)/Akt signalling, which in turn results in inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) and in doing so prevents the formation of a DSGIS motif-containing phosphodegron in Nrf2 that is recognized by the β-transducin repeat-containing protein (β-TrCP) Cul1-based E3 ubiquitin ligase complex SCF(β-TrCP). We present data showing that in the absence of Keap1, the electrophile tert-butyl hydroquinone (tBHQ) can stimulate Nrf2 activity and induce the Nrf2-target gene
  quinone oxidoreductase-1 (NQO1), whilst simultaneously causing inhibitory phosphorylation of GSK-3β at Ser(9). Together, these observations suggest that tBHQ can suppress the ability of SCF(β-TrCP) to target Nrf2 for proteasomal degradation by increasing PI3K-PKB/Akt signalling. We also propose a scheme that explains how other protein kinases that inhibit GSK-3 could stimulate induction of Nrf2-target genes by preventing formation of the DSGIS motif-containing phosphodegron in Nrf2.
authors.affiliation: Jacqui Wood Cancer Centre, Division of Cancer Research, University of Dundee, Dundee DD1 9SY, Scotland, U.K. j.d.hayes@dundee.ac.uk.
authors.forename: John D
authors.initials: JD
authors.lastname: Hayes
authors.affiliation: Jacqui Wood Cancer Centre, Division of Cancer Research, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Chowdhry
authors.affiliation: Jacqui Wood Cancer Centre, Division of Cancer Research, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
authors.forename: Calum
authors.initials: C
authors.lastname: Sutherland
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000737:chemistry / Q000378:metabolism*; D018384:Oxidative Stress; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
chemical_list: D000975:Antioxidants; C471644:BTRC protein, human; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D044844:beta-Transducin Repeat-Containing Proteins; D038362:Glycogen Synthase Kinase 3
keywords: NF-E2 p45-related factor 2 (Nrf2); epidermal growth factor; glycogen synthase kinase-3 (GSK-3); keratinocyte growth factor; phosphoinositide 3-kinase (PI3K); protein kinase B (PKB)/Akt; β-transducin repeat-containing protein (β-TrCP)