Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response
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In response to oxidative stress, Nrf2 and p21(Cip1/WAF1) are both upregulated to protect cells from oxidative damage. Nrf2 is constantly ubiquitinated by a Keap1 dimer that interacts with a weak-binding (29)DLG motif and a strong-binding (79)ETGE motif in Nrf2, resulting in degradation of Nrf2. Modification of the redox-sensitive cysteine residues on Keap1 disrupts the Keap1-(29)DLG binding, leading to diminished Nrf2 ubiquitination and activation of the antioxidant response. However, the underlying mechanism by which p21 protects cells from oxidative damage remains unclear. Here we present molecular and genetic evidence suggesting that the antioxidant function of p21 is mediated through activation of Nrf2 by stabilizing the Nrf2 protein. The (154)KRR motif in p21 directly interacts with the (29)DLG and (79)ETGE motifs in Nrf2 and thus competes with Keap1 for Nrf2 binding, compromising ubiquitination of Nrf2. Furthermore, the physiological significance of our findings was demonstrated in vivo using p21-deficient mice.
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The 154KRR156 motif within p21 directly binds to the DLG and ETGE motifs in Nrf2, competing with Keap1 for Nrf2 binding, and p21-Nrf2 binding leads to Nrf2 stabilization and increased response to oxidative stress.
“The 154KRR156 motif within p21 directly binds to the DLG and ETGE motifs in Nrf2, thereby competing with Keap1 for Nrf2 binding [26]; but instead of Nrf2 degradation, p21-Nrf2 binding leads to Nrf2 stabilization and increased response to oxidative stress [26].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [26]
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- Authors
- Chen, W., Sun, Z., Wang, X.-J., Jiang, T., Huang, Z., Fang, D., & Zhang, D. D.
- Affiliations
- University of Arizona (US)
- University of Missouri (US)
- Corresponding author
- Zhang, Donna D.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 34
- Issue
- 6
- Pages
- 663-673
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2714804
- OpenAlex
- W2080155284
- Cited by
- 638
- References
- 36
- Citations by year
- 2026: 24 · 2025: 15 · 2024: 50 · 2023: 31 · 2022: 43 · 2021: 51 · 2020: 48 · 2019: 52 · 2018: 48 · 2017: 35 · 2016: 44 · 2015: 29 · 2014: 40 · 2013: 38 · 2012: 34
- FWCI
- 11.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1543 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Cancer Society (ES006694, RSG-07-154)
- National Institute of Environmental Health Sciences (ES015010)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- Nrf2, p21, Keap1, oxidative stress, antioxidant response, protein stabilization, ubiquitination, protein-protein interaction
- MeSH terms
- Animals, Antioxidants, Binding Sites, Male, Up-Regulation, Oxidative Stress, Amino Acid Motifs, Cyclin-Dependent Kinase Inhibitor p21, NF-E2-Related Factor 2, Mice, Ubiquitination
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