Regulation of the CNC-bZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-TrCP

John D. Hayes, Kimimuepigha Ebisine, Ritu S. Sharma, Sudhir Chowdhry, Albena T. Dinkova-Kostova, Calum Sutherland

Research output: Contribution to journalReview article

Abstract

The transcription factor NF-E2 p45-related factor 2 (Nrf2) mediates adaptation to oxidative stress by inducing cytoprotective genes including heme oxygenase-1 (HMOX1) and NAD(P)H:quinone oxidoreductase-1 (NQO1). Nrf2 is principally controlled by Kelch-like ECH-associated protein 1 (Keap1), which allows constitutive ubiquitylation and rapid degradation of Nrf2 by the cullin-3 (Cul3)-RING ubiquitin ligase CRLKeap1 under non-stressed conditions. Simultaneously, glycogen synthase kinase-3 (GSK-3) also negatively controls Nrf2 through phosphorylation of a DSGIS-containing destruction motif in Nrf2, which then allows binding by β-transducin repeat-containing protein (β-TrCP) and ubiquitylation of the transcription factor by the Skp1−Cul1−F-box (SCF) ubiquitin ligase designated SCFβ-TrCP. It is well documented that oxidative stressors activate Nrf2 by antagonizing Keap1. We now show that both tert-butyl hydroquinone (tBHQ) and diethyl maleate (DEM), but not sulforaphane, induce Hmox1 and Nqo1 in Keap1−/− mouse embryonic fibroblasts (MEFs). Moreover, expression of Hmox1 and Nqo1 in Keap1−/− MEFs is substantially blunted by inhibition of either phosphoinositide 3-kinase (PI3K, using LY294002) or protein kinase B (PKB/Akt, using MK-2206), whereas inhibition of GSK-3 (using CT99021) induces expression of Hmox1 and Nqo1. Herein, we provide evidence that Nrf2 is subject to repression by both Keap1 and the axis between GSK-3 and β-TrCP. One likely scenario is that loss of the phosphatidylinositol (3,4,5)-trisphosphate (PIP3) 3-phosphatase activity of PTEN caused by tBHQ and DEM results in an increase in the levels of PIP3 produced by PI3K, and hence 3-phosphoinositide-dependent protein kinase-1 (PDK1) activity, which then stimulates PKB/Akt signaling.

Original languageEnglish (US)
Pages (from-to)92-103
Number of pages12
JournalCurrent Opinion in Toxicology
Volume1
DOIs
StatePublished - 2016
Externally publishedYes

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NF-E2-Related Factor 2
Basic-Leucine Zipper Transcription Factors
Glycogen Synthase Kinase 3
diethyl maleate
Fibroblasts
Ligases
Ubiquitin
Phosphatidylinositol 3-Kinases
NF-E2 Transcription Factor
3-Phosphoinositide-Dependent Protein Kinases
Proteins
Cullin Proteins
Transducin
Ubiquitination
Proto-Oncogene Proteins c-akt
Phosphorylation
Heme Oxygenase-1
Oxidative stress
Phosphatidylinositols
Phosphoric Monoester Hydrolases

Keywords

  • GSK-3
  • Keap1
  • Nrf2
  • PI3K
  • PKB/Akt
  • PTEN
  • β-TrCP

ASJC Scopus subject areas

  • Toxicology

Cite this

Hayes, J. D., Ebisine, K., Sharma, R. S., Chowdhry, S., Dinkova-Kostova, A. T., & Sutherland, C. (2016). Regulation of the CNC-bZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-TrCP. Current Opinion in Toxicology, 1, 92-103. https://doi.org/10.1016/j.cotox.2016.10.003

Regulation of the CNC-bZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-TrCP. / Hayes, John D.; Ebisine, Kimimuepigha; Sharma, Ritu S.; Chowdhry, Sudhir; Dinkova-Kostova, Albena T.; Sutherland, Calum.

In: Current Opinion in Toxicology, Vol. 1, 2016, p. 92-103.

Research output: Contribution to journalReview article

Hayes, JD, Ebisine, K, Sharma, RS, Chowdhry, S, Dinkova-Kostova, AT & Sutherland, C 2016, 'Regulation of the CNC-bZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-TrCP', Current Opinion in Toxicology, vol. 1, pp. 92-103. https://doi.org/10.1016/j.cotox.2016.10.003
Hayes, John D. ; Ebisine, Kimimuepigha ; Sharma, Ritu S. ; Chowdhry, Sudhir ; Dinkova-Kostova, Albena T. ; Sutherland, Calum. / Regulation of the CNC-bZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-TrCP. In: Current Opinion in Toxicology. 2016 ; Vol. 1. pp. 92-103.
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AU - Hayes, John D.

AU - Ebisine, Kimimuepigha

AU - Sharma, Ritu S.

AU - Chowdhry, Sudhir

AU - Dinkova-Kostova, Albena T.

AU - Sutherland, Calum

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N2 - The transcription factor NF-E2 p45-related factor 2 (Nrf2) mediates adaptation to oxidative stress by inducing cytoprotective genes including heme oxygenase-1 (HMOX1) and NAD(P)H:quinone oxidoreductase-1 (NQO1). Nrf2 is principally controlled by Kelch-like ECH-associated protein 1 (Keap1), which allows constitutive ubiquitylation and rapid degradation of Nrf2 by the cullin-3 (Cul3)-RING ubiquitin ligase CRLKeap1 under non-stressed conditions. Simultaneously, glycogen synthase kinase-3 (GSK-3) also negatively controls Nrf2 through phosphorylation of a DSGIS-containing destruction motif in Nrf2, which then allows binding by β-transducin repeat-containing protein (β-TrCP) and ubiquitylation of the transcription factor by the Skp1−Cul1−F-box (SCF) ubiquitin ligase designated SCFβ-TrCP. It is well documented that oxidative stressors activate Nrf2 by antagonizing Keap1. We now show that both tert-butyl hydroquinone (tBHQ) and diethyl maleate (DEM), but not sulforaphane, induce Hmox1 and Nqo1 in Keap1−/− mouse embryonic fibroblasts (MEFs). Moreover, expression of Hmox1 and Nqo1 in Keap1−/− MEFs is substantially blunted by inhibition of either phosphoinositide 3-kinase (PI3K, using LY294002) or protein kinase B (PKB/Akt, using MK-2206), whereas inhibition of GSK-3 (using CT99021) induces expression of Hmox1 and Nqo1. Herein, we provide evidence that Nrf2 is subject to repression by both Keap1 and the axis between GSK-3 and β-TrCP. One likely scenario is that loss of the phosphatidylinositol (3,4,5)-trisphosphate (PIP3) 3-phosphatase activity of PTEN caused by tBHQ and DEM results in an increase in the levels of PIP3 produced by PI3K, and hence 3-phosphoinositide-dependent protein kinase-1 (PDK1) activity, which then stimulates PKB/Akt signaling.

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