Cited by 617Genomics, phytochemicals, and oxidative stressGlutathione Transferases and PolymorphismsRedox biology and oxidative stress

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Increased Protein Stability as a Mechanism That Enhances Nrf2-mediated Transcriptional Activation of the Antioxidant Response Element

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Nguyen, Truyen, Sherratt, Philip J., Huang, H.-C., Yang, Chung S., Pickett, Cecil B.·2003·Journal of Biological Chemistry

DOI 10.1074/jbc.m207293200

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Abstract

Nrf2 (NF-E2-related factor 2) is a central transcription factor involved in the transcriptional activation of many genes encoding phase II drug-metabolizing enzymes via the antioxidant response element. Nrf2 has previously been found to undergo nuclear translocation by a phosphorylation-dependent mechanism mediated by protein kinase C in HepG2 cells treated with tert-butylhydroquinone, beta-naphthoflavone, or 12-O-tetradecanoylphorbol-13-acetate. In the present report, we have found that the levels of Nrf2 were increased in cells treated with tert-butylhydroquinone or beta-naphthoflavone by a post-transcriptional mechanism. Treatment of HepG2 cells with cycloheximide resulted in the loss of Nrf2 within 30 min. By contrast, treatment with the proteasome inhibitors (lactacystin or MG-132) caused an accumulation of Nrf2 as well as an induction of reporter gene activity in cells transfected with the GSTA2 antioxidant response element-chloramphenicol acetyl transferase construct. Similarly, the protein phosphatase inhibitor okadaic acid also caused an accumulation of Nrf2, whereas the reverse effects were observed with PD 98059 and U 0126, two compounds that block the activation of the MAPK/ERK signaling cascade. These data suggest that Nrf2 is degraded by the ubiquitin-dependent pathway and that phosphorylation of Nrf2 leads to an increase in its stability and subsequent transactivation activity.

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Authors: Nguyen, T., Sherratt, P. J., Huang, H.-C., Yang, C. S., & Pickett, C. B.
Affiliations: Rutgers, The State University of New Jersey (US)
Corresponding author: Pickett, Cecil B.
ORCID: Yang, Chung S.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2003-02
Volume: 278
Issue: 7
Pages: 4536-4541
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m207293200
OpenAlex: W2080435498
Cited by: 615
References: 44
Citations by year: 2026: 15 · 2025: 13 · 2024: 24 · 2023: 25 · 2022: 29 · 2021: 25 · 2020: 24 · 2019: 31 · 2018: 23 · 2017: 24 · 2016: 29 · 2015: 31 · 2014: 21 · 2013: 31 · 2012: 36
FWCI: 12.29
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6452 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: Nrf2, antioxidant response element, protein stability, ubiquitin-mediated proteolysis, Nrf2 phosphorylation, phase II enzymes, tert-butylhydroquinone, beta-naphthoflavone, proteasome inhibitors, ERK signaling, protein phosphatase, transcriptional activation, HepG2 cells
MeSH terms: Antioxidants, Butadienes, Cell Line, DNA-Binding Proteins, Enzyme Inhibitors, Flavonoids, Humans, Hydroquinones, Nitriles, Peptide Hydrolases, Phosphorylation, RNA Processing, Post-Transcriptional, Transcriptional Activation, Trans-Activators, Leucine Zippers, Oxidative Stress, beta-Naphthoflavone, Protein Subunits, Proteasome Endopeptidase Complex, NF-E2-Related Factor 2

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Increased Protein Stability as a Mechanism That Enhances Nrf2-mediated Transcriptional Activation of the Antioxidant Response Element

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