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

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

613 citations recorded by the source corpus.

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 withtert-butylhydroquinone, β-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 β-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 theGSTA2 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.

Subfields: Biochemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e4196d3761f7743d54c9d6b838ae9c352d81c0b8

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Citations in the corpus

The cytoprotective role of the Keap1–Nrf2 pathway (2011, background): “…however, all studies that showed an increase in Nrf2 stability in response to inducers found that even in the presence of these chemicals, Nrf2 still has a half-life between 30 and 100 min, suggesting it is still rapidly turned over (Stewart et al. 2003; Nguyen et al. 2003; McMahon et al. 2004).”
Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022, background): “Under basal conditions, Nrf2 has a short half-life of only 10–30 min [50,77].”
Induction of phase I, II and III drug metabolism/transport by xenobiotics (2005, background): “…mRNA level in certain cell types, but attenuated ubiquitination and proteosomal degradation of Nrf2, implying that the activity of Nrf2 may not be determined transciptionally but perhaps post-translationally, at least in these cells types (Alam et aL, 2003; Nguyen et aL, 2003; Stewart et aL, 2003).”
Transcriptional Regulation by Nrf2 (2017, background): “Under unperturbed conditions, Nrf2 has a short halflife of approximately 10–30 min; therefore, Keap1-mediated high turnover of Nrf2 keeps Nrf2 basal levels extremely low (118, 156).”
Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. (2012, background): “Nrf2 is principally controlled through protein ubiquitylation, which targets it for proteasomal degradation (4-6).”
SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. (2003, neutral): “( Itoh et al. 1999; Sekhar et al. 2002; Nguyen et al. 2003; Stewart et al. 2003).”
The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. (2013, background): “of Nrf2 activation [37].”
Oxidative and Electrophilic Stresses Activate Nrf2 through Inhibition of Ubiquitination Activity of Keap1 (2006, background): “This rapid turnover of Nrf2 prevents the unnecessary expression of Nrf2 target genes (16, 27, 30, 38).”