The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2
Open accessAbstract
The risks of cancer and other degenerative diseases caused by reactive oxygen species and electrophiles can be reduced by the up-regulation of detoxifying enzymes. A major mechanism whereby these protective enzymes are induced occurs through activation of the antioxidant response element (ARE) by the oxidative-stress sensor protein Kelch-like ECH-associated protein 1 (Keap1) and the transcription factor NF-E2-related factor 2 (Nrf2). Under basal conditions, Keap1 sequesters Nrf2 in the cytoplasm by binding to its Neh2 domain. Chemical inducers such as sulforaphane are known to react with Keap1 cysteine residues, thereby promoting Nrf2 nuclear accumulation and hence ARE activation. A widely accepted model for Nrf2 nuclear accumulation is that modification of Keap1 cysteines leads directly to dissociation of the Keap1-Nrf2 complex. This model is based on studies with mouse proteins and has served as the experimental basis and hypothesis for numerous investigations. Through a combination of chemical, mass spectrometry, and isothermal titration calorimetry methods, we have tested the direct-dissociation model using a series of ARE inducers: sulforaphane, isoliquiritigenin, 15-deoxy-Δ12,14-prostaglandin-J2, menadione, 1-Cl-2,4-dinitrobenzene, and biotinylated iodoacetamide. Surprisingly, these data suggest that the direct disruption model for Keap1-Nrf2 is incorrect. The relative reactivity of human Keap1 cysteines was determined. In addition to the same five cysteines identified for mouse Keap1, two highly reactive and previously unobserved cysteines were identified. Based on these results, a model is proposed that should aid in the understanding of Keap1-Nrf2 signaling mechanisms.
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Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex
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The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm
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Ma, Q. (2013) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011112-140320 · Cited by 4,903
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D'Autréaux, B., & Toledano, M. B. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2256 · Cited by 3,642
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Nguyen, T., Nioi, P., & Pickett, C. B. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.r900010200 · Cited by 2,655
Combination therapy in combating cancer
Mokhtari, R. B., Homayouni, T. S., Baluch, N., Morgatskaya, E., Kumar, S., Das, B., & Yeger, H. (2017) · Oncotarget · doi:10.18632/oncotarget.16723 · Cited by 2,543
Nrf2:INrf2 (Keap1) signaling in oxidative stress
Kaspar, J. W., Niture, S. K., & Jaiswal, A. K. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.07.035 · Cited by 1,648
Metadata
- Authors
- Eggler, A. L., Liu, G., Pezzuto, J. M., van Breemen, R. B., & Mesecar, A. D.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2005-07-08
- Volume
- 102
- Issue
- 29
- Pages
- 10070-10075
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2114101650
- Cited by
- 456
- References
- 9
- FWCI
- 9.10
- Type
- journal article
- Language
- en
- Open access
- green
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- Eggler, A. L., Liu, G., Pezzuto, J. M., van Breemen, R. B., & Mesecar, A. D. (2005). Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0502402102
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