The DOI matches its Crossref record; 34 of the 36 references it cites were found in a registry or an index.
Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M. (1999) · Genes & Development · doi:10.1101/gad.13.1.76 · Cited by 3,634
Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141046 · Cited by 3,630
Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224
Zhang, D. D., & Hannink, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.22.8137-8151.2003 · Cited by 1,480
Self-citationKeap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex
Zhang, D. D., Lo, S., Cross, J. V., Templeton, D. J., & Hannink, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.24.10941-10953.2004 · Cited by 1,284
Self-citationMcMahon, M., Itoh, K., Yamamoto, M., & Hayes, J. D. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300931200 · Cited by 1,141
Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway
Zhang, D. D. (2006) · Drug Metabolism Reviews · doi:10.1080/03602530600971974 · Cited by 1,105
Self-citationRamos-Gomez, M., Kwak, M.-K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P., & Kensler, T. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051618798 · Cited by 1,102
Molecular Mechanisms Activating the Nrf2-Keap1 Pathway of Antioxidant Gene Regulation
Kobayashi, M., & Yamamoto, M. P. (2005) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.385 · Cited by 1,087
Wakabayashi, N., Dinkova-Kostova, A. T., Holtzclaw, W. D., Kang, M.-I., Kobayashi, A., Yamamoto, M., Kensler, T. W., & Talalay, P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307301101 · Cited by 986
Kobayashi, A., Kang, M.-I., Watai, Y., Tong, K. I., Shibata, T., Uchida, K., & Yamamoto, M. P. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.26.1.221-229.2006 · Cited by 947
The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage
Gong, J., Costanzo, A., Yang, H., Melino, G., Kaelin, W. G., Levrero, M., & Wang, J. Y. J. (1999) · Nature · doi:10.1038/21690 · Cited by 923
The role of the cyclin-dependent kinase inhibitor p21 in apoptosis.
Gartel, A. L., & Tyner, A. L. (2002) · PubMed · Cited by 918
Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2
Wang, X.-J., Sun, Z., Villeneuve, N. F., Zhang, S., Zhao, F., Li, Y., Chen, W., Yi, X., Zheng, W., Wondrak, G. T., et al. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn095 · Cited by 839
Self-citationTong, K. I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T., & Yamamoto, M. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.8.2887-2900.2006 · Cited by 759 · cited 6×
“It is believed that the Keap1 homodimer binds both the 29 DLG and 79 ETGE motifs in Nrf2 to align the seven ubiquitin-accepting lysine residues between these motifs into a conformation suitable for ubiquitin conjugation (McMahon et al., 2006; Tong et al., 2006, 2007; Zhang et al., 2004).”
BackgroundInfluentialStructural basis for defects of Keap1 activity provoked by its point mutations in lung cancer
Padmanabhan, B., Tong, K. I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.-I., Kobayashi, A., Yokoyama, S., & Yamamoto, M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.013 · Cited by 735 · cited 1×
“The Kelch domain contains six conserved Kelch repeats that form a six-bladed b-propeller structure (Li et al., 2004; Padmanabhan et al., 2006).”
BackgroundLAU, A., VILLENEUVE, N., Sun, Z., Wong, P. K., & Zhang, D. (2008) · Pharmacological Research · doi:10.1016/j.phrs.2008.09.003 · Cited by 653
Self-citationDifferential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair
Li, R., Waga, S., Hannon, G. J., Beach, D., & Stillman, B. (1994) · Nature · doi:10.1038/371534a0 · Cited by 645
Physiological Significance of Reactive Cysteine Residues of Keap1 in Determining Nrf2 Activity
Yamamoto, T., Suzuki, T., Kobayashi, A., Wakabayashi, J., Maher, J. M., Motohashi, H., & Yamamoto, M. P. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01704-07 · Cited by 515
McMahon, M. J., Thomas, N., Itoh, K., Yamamoto, M. P., & Hayes, J. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601119200 · Cited by 495
p21WAF1/Cip1: more than a break to the cell cycle?
Dotto, G. P. (2000) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(00)00019-6 · Cited by 470
Tong, K. I., Padmanabhan, B., Kobayashi, A., Shang, C., Hirotsu, Y., Yokoyama, S., & Yamamoto, M. P. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00753-07 · Cited by 459
The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm
Zipper, L. M., & Mulcahy, R. T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206530200 · Cited by 366
The transcription factor NRF2 protects against pulmonary fibrosis
Cho, H., Reddy, S. P., Yamamoto, M. P., & Kleeberger, S. R. (2004) · The FASEB Journal · doi:10.1096/fj.03-1127fje · Cited by 355
Sun, Z., Zhang, S., Chan, J. Y., & Zhang, D. D. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00630-07 · Cited by 332
Self-citationHayes, J. D., Chanas, S. A., Henderson, C. J., McMahon, M. J., Sun, C., Moffat, G. J., Wolf, C. R., & Yamamoto, M. P. (2000) · Biochemical Society Transactions · doi:10.1042/bst0280033 · Cited by 321
Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust
Aoki, Y., Sato, H., Nishimura, N., Takahashi, S., Itoh, K., & Yamamoto, M. (2001) · Toxicology and Applied Pharmacology · doi:10.1006/taap.2001.9176 · Cited by 297
Crystal Structure of the Kelch Domain of Human Keap1
Li, X., Zhang, D., Hannink, M., & Beamer, L. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410073200 · Cited by 256
Self-citationChild, E. S., & Mann, D. J. (2006) · Cell Cycle · doi:10.4161/cc.5.12.2863 · Cited by 185
The Cyclin-Dependent Kinase Inhibitor p21 Protects the Lung from Oxidative Stress
O’Reilly, M. A., Staversky, R. J., Watkins, R. H., Reed, C. K., Jensen, K. L. D. M., Finkelstein, J. N., & Keng, P. C. (2001) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.24.6.4355 · Cited by 111
Redox Activation of p21 Cip1/WAF1/Sdi1 : A Multifunctional Regulator of Cell Survival and Death
O’Reilly, M. A. (2004) · Antioxidants and Redox Signaling · doi:10.1089/ars.2005.7.108 · Cited by 98
Nrf2 protects human bladder urothelial cells from arsenite and monomethylarsonous acid toxicity
Wang, X.-J., Sun, Z., Chen, W., Eblin, K. E., Gandolfi, J. A., & Zhang, D. D. (2007) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2007.07.016 · Cited by 98
Self-citationExpression of a novel form of p21Cip1/Waf1 in UV-irradiated and transformed cells
Poon, R. Y. C., & Hunter, T. (1998) · Oncogene · doi:10.1038/sj.onc.1201897 · Cited by 54
A new p21waf1/cip1 isoform is an early event of cell response to oxidative stress
Esposito, F., Cuccovillo, F., Russo, L., Casella, F., Russo, T., & Cimino, F. (1998) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400427 · Cited by 29
Cited by
Sorted by citations
Role of nrf2 in oxidative stress and toxicity
Ma, Q. (2013) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011112-140320 · Cited by 4,903
Regulation of cancer cell metabolism
Cairns, R. A., Harris, I. S., & Mak, T. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2981 · Cited by 4,744
Modulation of oxidative stress as an anticancer strategy
Gorrini, C., Harris, I. S., & Mak, T. W. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4002 · Cited by 3,579
Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy
Forman, H. J., & Zhang, H. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00233-1 · Cited by 2,900
Transcriptional Regulation by Nrf2
Tonelli, C., Chio, I. I. C., & Tuveson, D. A. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7342 · Cited by 2,280
Metadata
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
