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

John D. Hayes (Lead / Corresponding author), Sudhir Chowdhry, Albena T. Dinkova-Kostova, Calum Sutherland

    Research output: Contribution to journalArticlepeer-review

    61 Citations (Scopus)

    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<sup>Keap1</sup>. 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<sup>β-TrCP</sup>. 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<sup>9</sup>. Together, these observations suggest that tBHQ can suppress the ability of SCF<sup>β-TrCP</sup> 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.

    Original languageEnglish
    Pages (from-to)611-620
    Number of pages10
    JournalBiochemical Society Transactions
    Volume43
    Issue number4
    Early online date3 Aug 2015
    DOIs
    Publication statusPublished - Aug 2015

    Keywords

    • Epidermal growth factor
    • Glycogen synthase kinase-3 (GSK-3)
    • Keratinocyte growth factor
    • NF-E2 p45-related factor 2 (Nrf2)
    • Phosphoinositide 3-kinase (PI3K)
    • Protein kinase B (PKB)/Akt
    • β-transducin repeat-containing protein (β-TrCP)

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