The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.
Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex
Open accessAbstract
The bZIP transcription factor Nrf2 controls a genetic program that protects cells from oxidative damage and maintains cellular redox homeostasis. Keap1, a BTB-Kelch protein, is the major upstream regulator of Nrf2 and controls both the subcellular localization and steady-state levels of Nrf2. In this report, we demonstrate that Keap1 functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 assembles into a functional E3 ubiquitin ligase complex with Cul3 and Rbx1 that targets multiple lysine residues located in the N-terminal Neh2 domain of Nrf2 for ubiquitin conjugation both in vivo and in vitro. Keap1-dependent ubiquitination of Nrf2 is inhibited following exposure of cells to quinone-induced oxidative stress and sulforaphane, a cancer-preventive isothiocyanate. A mutant Keap1 protein containing a single cysteine-to-serine substitution at residue 151 within the BTB domain of Keap1 is markedly resistant to inhibition by either quinone-induced oxidative stress or sulforaphane. Inhibition of Keap1-dependent ubiquitination of Nrf2 correlates with decreased association of Keap1 with Cul3. Neither quinone-induced oxidative stress nor sulforaphane disrupts association between Keap1 and Nrf2. Our results suggest that the ability of Keap1 to assemble into a functional E3 ubiquitin ligase complex is the critical determinant that controls steady-state levels of Nrf2 in response to cancer-preventive compounds and oxidative stress.
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“3 g, lanes 2 to 5), and Cul3(1-380) (from 0.”
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“Talalay and coworkers have identified four cysteine residues in Keap1 (Cys 257, Cys 273, Cys 288, and Cys 297) that are preferentially labeled following in vitro exposure of purified Keap1 to a cysteine-reactive alkylating agent (16, 52).”
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Stewart, D., Killeen, E., Naquin, R., Alam, S., & Alam, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m209195200 · Cited by 463
Cited by
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
ROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis
D'Autréaux, B., & Toledano, M. B. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2256 · Cited by 3,642
The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress
Nguyen, T., Nioi, P., & Pickett, C. B. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.r900010200 · Cited by 2,655
Komatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y.-S., Ueno, I., Sakamoto, A., Tong, K. I., et al. (2010) · Nature Cell Biology · doi:10.1038/ncb2021 · Cited by 2,288
The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00023.2017 · Cited by 1,968
Metadata
- Authors
- Zhang, D. D., Lo, S.-C., Cross, J. V., Templeton, D. J., & Hannink, M.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2004-12-01
- Volume
- 24
- Issue
- 24
- Pages
- 10941-10953
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2168395641
- Cited by
- 1,254
- References
- 13
- FWCI
- 9.73
- Type
- journal article
- Language
- en
- Open access
- green
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