Functional polymorphisms in Nrf2: implications for human disease

Cho, Hye‐Youn; Marzec, Jacqui; Kleeberger, Steven R.

doi:10.1016/j.freeradbiomed.2015.06.012

Cited by 67 publications

(52 citation statements)

References 78 publications

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“…Functional polymorphisms in NFE2L2 that diminish expression of Nrf2 have been linked with several diseases [reviewed in ref. (90)]. Nrf2 transactivation is subject to epigenetic regulation that can be suppressed, with a consequence of inhibiting Nrf2 target gene expression (1,91–93).…”

Section: Resultsmentioning

confidence: 99%

The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

et al. 2018

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The transcription factor Nrf2 is an important modulator of antioxidant and drug metabolism, carbohydrate and lipid metabolism, as well as heme and iron metabolism. Regulation of Nrf2 expression occurs transcriptionally and post-transcriptionally. Post-transcriptional regulation entails ubiquitination followed by proteasome-dependent degradation. Additionally, Nrf2-mediated gene expression is subject to negative regulation by ATF3, Bach1 and cMyc. Nrf2-mediated gene expression is an important regulator of a cell’s response to radiation. Although a majority of studies have shown that Nrf2 deficient cells are radiosensitized and Nrf2 over expression confers radioresistance, Nrf2’s role in mediating the radiation response of crypt cells is controversial. The Nrf2 activator CDDO attenuates radiation-mediated crypt injury, whereas intestinal crypts in Nrf2 null mice are radiation resistant. Further investigation is needed in order to define the relationship between Nrf2 and radiation sensitivity in Lgr5+ and Bmi1+ cells that regulate regeneration of crypt stem cells. In hematopoietic compartments Nrf2 promotes the survival of irradiated osteoblasts that support long-term hematopoietic stem cell (LT-HSC) niches. Loss of Nrf2 in LT-HSCs increases stem cell intrinsic radiosensitivity, with the consequence of lowering the LD5030. An Nrf2 deficiency drives LT-HSCs from a quiescent to a proliferative state. This results in hematopoietic exhaustion and reduced engraftment after myoablative irradiation. The question of whether induction of Nrf2 in LT-HSC enhances hematopoietic reconstitution after bone marrow transplantation is not yet resolved. Irradiation of the lung induces pulmonary pneumonitis and fibrosis. Loss of Nrf2 promotes TGF-β/Smad signaling that induces ATF3 suppression of Nrf2-mediated target gene expression. This, in turn, results in elevated reactive oxygen species (ROS) and isolevuglandin adduction of protein that impairs collagen degradation, and may contribute to radiation-induced chronic cell injury. Loss of Nrf2 impairs ΔNp63 stem/progenitor cell mobilization after irradiation, while promoting alveolar type 2 cell epithelial-mesenchymal transitions into myofibroblasts. These studies identify Nrf2 as an important factor in the radiation response of normal tissue.

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Section: Resultsmentioning

confidence: 99%

The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

et al. 2018

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“…7 E ). This study has significant clinical relevance because of the association of Nrf2 and MT gene polymorphisms for several diseases, including cardiovascular diseases (45,46). Once we refine the relationship of Nrf2 with MT in diabetes, we can explore strategies that upregulate MT and/or Nrf2 for patients with genetic polymorphisms, such as via SFN and/or zinc to induce cardiac protection.…”

Section: Discussionmentioning

confidence: 99%

Metallothionein Is Downstream of Nrf2 and Partially Mediates Sulforaphane Prevention of Diabetic Cardiomyopathy

et al. 2016

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We have reported that sulforaphane (SFN) prevented diabetic cardiomyopathy in both type 1 and type 2 diabetes (T2DM) animal models via the upregulation of nuclear transcription factor erythroid 2–related factor 2 (Nrf2) and metallothionein (MT). In this study, we tested whether SFN protects the heart from T2DM directly through Nrf2, MT, or both. Using Nrf2-knockout (KO), MT-KO, and wild-type (WT) mice, T2DM was induced by feeding a high-fat diet for 3 months followed by a small dose of streptozotocin. Age-matched controls were given a normal diet. Both T2DM and control mice were then treated with or without SFN for 4 months by continually feeding a high-fat or normal diet. SFN prevented diabetes-induced cardiac dysfunction as well as diabetes-associated cardiac oxidative damage, inflammation, fibrosis, and hypertrophy, with increases in Nrf2 and MT expressions in the WT mice. Both Nrf2-KO and MT-KO diabetic mice exhibited greater cardiac damage than WT diabetic mice. SFN did not provide cardiac protection in Nrf2-KO mice, but partially or completely protected the heart from diabetes in MT-KO mice. SFN did not induce MT expression in Nrf2-KO mice, but stimulated Nrf2 function in MT-KO mice. These results suggest that Nrf2 plays the indispensable role for SFN cardiac protection from T2DM with significant induction of MT and other antioxidants. MT expression induced by SFN is Nrf2 dependent, but is not indispensable for SFN-induced cardiac protection from T2DM.

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“…An excellent review on this topic reported in 2015 up to 18 single-nucleotide polymorphisms (SNPs), most of them in the 59 regulatory region and in intron 1 (Cho et al, 2015). Several of these SNPs might constitute functional haplotypes that are associated with risk at onset or progression of chronic diseases.…”

Section: B Positioning Nuclear Factor (Erythroid-derived 2)-like 2 Amentioning

confidence: 99%