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

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

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Jacqui Wood Cancer Centre, Division of Cancer Research, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
Jacqui Wood Cancer Centre, Division of Cancer Research, University of Dundee, Dundee DD1 9SY, Scotland, U.K.
Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, U.K.


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.


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)

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