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Cited by 534

The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.

Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes

Open access
Kang, Moon-Il, Kobayashi, Akira, Wakabayashi, Nobunao, Kim, Sang-Geon, Yamamoto, Masayuki·2004·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0308347100
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Abstract

Transcription factor Nrf2 regulates basal and inducible expression of phase 2 proteins that protect animal cells against the toxic effects of electrophiles and oxidants. Under basal conditions, Nrf2 is sequestered in the cytoplasm by Keap1, a multidomain, cysteinerich protein that is bound to the actin cytoskeleton. Keap1 acts both as a repressor of the Nrf2 transactivation and as a sensor of phase 2 inducers. Electrophiles and oxidants disrupt the Keap1–Nrf2 complex, resulting in nuclear accumulation of Nrf2, where it enhances the transcription of phase 2 genes via a common upstream regulatory element, the antioxidant response element. Reporter cotransfection–transactivation analyses with a series of Keap1 deletion mutants revealed that in the absence of the double glycine repeat domain Keap1 does not bind to Nrf2. In addition, deletion of either the intervening region or the C-terminal region also abolished the ability of Keap1 to sequester Nrf2, indicating that all of these domains contribute to the repressor activity of Keap1. Immunocytochemical and immunoprecipitation analyses demonstrated that Keap1 associates with actin filaments in the cytoplasm through its double glycine repeat domain. Importantly, disruption of the actin cytoskeleton promotes nuclear entry of an Nrf2 reporter protein. The actin cytoskeleton therefore provides scaffolding that is essential for the function of Keap1, which is the sensor for oxidative and electrophilic stress.

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Metadata

Authors
Kang, M.-I., Kobayashi, A., Wakabayashi, N., Kim, S.-G., & Yamamoto, M.
Venue
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Published
2004-02-05
Volume
101
Issue
7
Pages
2046-2051
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0308347100
OpenAlex
W2053919910
Cited by
534
References
9
FWCI
9.29
Type
journal article
Language
en
Open access
green

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CoChat. (2026). Citation check: Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. https://app.cochat.ai/papers/10.1073/pnas.0308347100
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Kang, M.-I., Kobayashi, A., Wakabayashi, N., Kim, S.-G., & Yamamoto, M. (2004). Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0308347100

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Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.