ArticleProceedings of the National Academy of Sciences of the United States of America2012
Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers, 1 of them a synthesis that pooled it.
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Who cites it
94 citing papers in PubMed, 1 synthesis or guideline pooled it, 152 citations in OpenAlex.
- Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review.Biochemical Society transactions · 2021Pooled it
- Bromodomain and extraterminal proteins suppress NF-E2-related factor 2-mediated antioxidant gene expression.Journal of immunology (Baltimore, Md. : 1950) · 2014Trial
- Low-dose X-ray radiation induces an adaptive response: A potential countermeasure to galactic cosmic radiation exposure.Experimental physiology · 2026Article
- Effects of Fractionated Low Dose Ionizing Radiation on Cellular Senescence in Mouse Lung Tissue.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Galactic cosmic radiation produces sex-specific, circuit-selective cognitive vulnerability: countermeasure trade-offs revealed by multi-domain assessment.Research square · 2026Article
- From metabolism to genome integrity: NRF2 as a key mediator of cancer therapy response.Frontiers in cell and developmental biology · 2026Review
- Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) as a Biomarker for Radiation Dosimetry and Health Risk Assessment: A Review.Antioxidants (Basel, Switzerland) · 2025Review
- Review
- The longitudinal behavioral effects of acute exposure to galactic cosmic radiation in female C57BL/6J mice: Implications for deep space missions, female crews, and potential antioxidant countermeasures.Journal of neurochemistry · 2025Article
- p53-dependent crosstalk between DNA replication integrity and redox metabolism mediated through a NRF2-PARP1 axis.Nucleic acids research · 2024Article
- NRF2 signaling pathway and telomere length in aging and age-related diseases.Molecular and cellular biochemistry · 2024Review
- Review
- NRF2 promotes radiation resistance by cooperating with TOPBP1 to activate the ATR-CHK1 signaling pathway.Theranostics · 2024Article
- Roles of NRF2 in DNA damage repair.Cellular oncology (Dordrecht, Netherlands) · 2023Review
- Nrf2 Drives Hepatocellular Carcinoma Progression through Acetyl-CoA-Mediated Metabolic and Epigenetic Regulatory Networks.Molecular cancer research : MCR · 2023Article
- Roles of Oxidative Stress and Nrf2 Signaling in Pathogenic and Non-Pathogenic Cells: A Possible General Mechanism of Resistance to Therapy.Antioxidants (Basel, Switzerland) · 2023Review
- Dimethyl Fumarate and Intestine: From Main Suspect to Potential Ally against Gut Disorders.International journal of molecular sciences · 2023Review
- Molecular and cellular basis of the dose-rate-dependent adverse effects of radiation exposure in animal models. Part I: Mammary gland and digestive tract.Journal of radiation research · 2023Review
- Stimulation of Nuclear Factor (Erythroid-Derived 2)-like 2 Signaling by Nucleus Targeted Irradiation with Proton Microbeam.Biology · 2023Article
- Epigenetic-Metabolic Interplay in the DNA Damage Response and Therapeutic Resistance of Breast Cancer.Cancer research · 2023Article
34 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator for antioxidant and anti-inflammation enzymes that binds to its endogenous inhibitor protein, Kelch-like ECH (erythroid cell-derived protein with CNC homology)-associated protein 1, in the cytoplasm under normal conditions. Various endogenous or environmental oxidative stresses, such as ionizing radiation (IR), can disrupt the Nrf2-Kelch-like ECH-associated protein 1 complex. This allows Nrf2 to translocate from the cytoplasm into the nucleus to induce transcription of heme oxygenase-1 and other cytoprotective enzymes through binding to antioxidant responsive elements. However, how Nrf2 protects cells from IR-induced damage remains unclear. Here, we report that Nrf2 activation by the synthetic triterpenoids, bardoxolone methyl (BARD) and 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid-ethyl amide, protects colonic epithelial cells against IR-induced damage, in part, by enhancing signaling of the DNA damage response. Pretreatment with BARD reduced the frequency of both G1 and S/G2 chromosome aberrations and enhanced the disappearance of repairosomes (C-terminal binding protein interacting protein, Rad51, and p53 binding protein-1 foci) after IR. BARD protected cells from IR toxicity in a Nrf2-dependent manner. The p53 binding protein-1 promoter contains three antioxidant responsive elements in which Nrf2 directly binds following BARD treatment. In addition, 2-cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid-ethyl amide provided before exposure to a lethal dose of whole-body irradiation protected WT mice from DNA damage and acute gastrointestinal toxicity, which resulted in improved overall survival. These results demonstrate that Nrf2 activation by synthetic triterpenoids is a promising candidate target to protect the gastrointestinal tract against acute IR in vitro and in vivo.
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