The Keap1/Nrf2 pathway in health and disease

NF-E2 p45-related factor 2 (Nrf2) is a master regulator of redox homeostasis 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  based E3 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 signaling, which in turn results in inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3), and in so doing prevents the formation of a DSGIS motif-containing phosphodegron in Nrf2 that is recognised by the  -transducin repeat-containing protein (  -TrCP) Cullin-1  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 (i.e. NQO1 ), whilst simultaneously causing inhibitory phosphorylation of GSK-3  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 signaling. 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