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Cited by 212Genomics, phytochemicals, and oxidative stressUbiquitin and proteasome pathwaysRedox biology and oxidative stress

A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity

Nioi, Paul, Nguyen, Truyen·2007·Biochemical and Biophysical Research Communications
DOI 10.1016/j.bbrc.2007.08.051
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Abstract

Keap1 is the substrate recognition module of a Cullin 3-based E3 ubiquitin ligase. Its primary role is to catalyze the ubiquitylation of the Nrf2 transcription factor. Oxidative stress blocks the E3 ligase activity of Keap1 which stabilizes Nrf2 allowing it to drive the expression of certain antioxidant and drug metabolizing enzymes. A recent study identified a mutation in the Keap1 gene (Keap1C23Y) that is present in breast cancer. Using reporter gene assays we show that Keap1C23Y is impaired in its ability to repress Nrf2 dependent transcription. Unlike wild-type Keap1, we found that Keap1C23Y failed to stimulate the degradation of Nrf2. Co-immunopreciptation experiments showed that Keap1C23Y retains its ability to interact with Nrf2 and Cullin 3. In contrast, we found that Keap1C23Y could not efficiently promote the ubiquitylation of Nrf2, suggesting that its intrinsic biological activity might have been compromised. These results revealed an unexpected role for the N-terminal region of Keap1 in regulating its E3 ligase activity. Importantly, our findings suggest that a paradox exists whereby Nrf2 activity is beneficial in non-malignant cells but in cancer cells it may provide a selective advantage for clonal expansion.

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  • Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance.

    “Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, thereby leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance (e.g., chemoresistance) (Figure 8) [161,162,163,164,165,166,167,168,169,170,171].”

    From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [167]

  • Most of these cancers' aberrant Nrf2 expression and poor prognosis have been attributed to loss-of-function mutations in KEAP1 and/or gain-of-function mutations in NFE2L2.

    “most of which have been attributed to loss-of-function mutations in the KEAP1 gene and/or gain-of-function mutations in the NFE2L2 gene encoding Nrf2 [162,163,164,166,167].”

    From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [167]

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Authors
Nioi, P., & Nguyen, T.
Corresponding author
Nioi, Paul
ORCID
Nioi, Paul
Venue
Biochemical and Biophysical Research Communications
Publisher
Elsevier BV
Published
2007-11
Volume
362
Issue
4
Pages
816-821
ISSN
0006-291X (ISSN-L)
DOI
10.1016/j.bbrc.2007.08.051
OpenAlex
W1972793256
Cited by
212
References
36
Citations by year
2026: 1 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 9 · 2021: 8 · 2020: 14 · 2019: 6 · 2018: 14 · 2017: 15 · 2016: 6 · 2015: 14 · 2014: 14 · 2013: 18 · 2012: 23
FWCI
5.03
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biochemical and Biophysical Research Communications (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
Keap1, Nrf2, breast cancer, Nrf2 degradation, oxidative stress, N-terminal domain, transcriptional repression, clonal expansion, antioxidant enzymes
MeSH terms
Kelch-Like ECH-Associated Protein 1, Breast Neoplasms, Humans, Mutation, Repressor Proteins, Mutagenesis, Site-Directed, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2

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