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

Biochem Soc Trans. 2015 Aug;43(4):611-20. doi: 10.1042/BST20150011. Epub 2015 Aug 3.


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

Nad(p)h: 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.

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).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antioxidants / pharmacology
  • Gene Expression Regulation / drug effects
  • Glycogen Synthase Kinase 3 / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2 / chemistry
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress
  • Protein Stability
  • Protein Structure, Tertiary
  • Signal Transduction / drug effects
  • beta-Transducin Repeat-Containing Proteins / metabolism*


  • Antioxidants
  • BTRC protein, human
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • beta-Transducin Repeat-Containing Proteins
  • Glycogen Synthase Kinase 3