Transcriptional Regulation by Nrf2

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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“…(13)] and post-translationally regulated (14). Under nonstress conditions, Nrf2 undergoes rapid ubiquitination and proteasome degradation (14).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Since nuclear accumulation of Nrf2 modulates the expression of a large number of genes, including familiar antioxidant enzymes, but also detoxification phase II enzymes, such as glutathione transferases (GST), changes in cellular redox balance in RCC might also be attributed to alterations in GST phenotype. Indeed, certain GSTs belong the Nrf2‐regulated cytoprotective defense system …”

Section: Altered Redox Homeostasis Underlying Rccmentioning

confidence: 99%

Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma

et al. 2019

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Renal cell carcinoma (RCC) represents a group of histologically similar neoplasms with significant intratumor and intertumor genetic heterogeneity. Recognized risk factors for RCC development include smoking, hypertension, obesity, as well as von Hippel–Lindau (VHL) disease. Inactivation of VHL, deregulated nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) pathway, and altered redox homeostasis, together with changes in glutathione transferase (GST) profile, are considered as important contributing factors in RCC development and progression. Although the available results of both gene–gene and gene–environment analysis are quite heterogeneous, they clearly indicate that certain GST genotypes may play a role as risk modifiers, either individually or in combination with other Phase I or Phase II gene polymorphisms, as well as in subjects exposed to relevant substrates. Seemingly, GST genotyping could identify individuals with impaired detoxification in renal parenchyma that are at higher risk of developing RCC. In addition to well established roles of GSTs in conjugation and biotransformation of xenobiotics, GSTs have emerged as significant regulators of pathways determining cell proliferation and survival. Indeed, there are evidence in favor of GST significance, not only in terms of risk for RCC development, but also with respect to progression and prognosis. So far, GSTM1‐active genotype was confirmed to be an independent predictor of higher risk of overall mortality. Therefore, it is reasonable to assume that certain GST variants may assist in individual RCC risk assessment, as well as postoperative prognosis. Even more, GST profiling might contribute to development of personalized targeted therapy in RCC patients.

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“…Representing the outermost surface of the body, skin is uniquely vulnerable to a plethora of environmental insults. Exposure to harmful chemicals, xenobiotics, oxidative stress, and solar UV‐radiation is mitigated by various protective mechanisms that rely on signaling networks and the expression of proteins involved in the detoxification of compounds or reactive oxygen species (Dinkova‐Kostova et al, ; Dodson et al, ; Hiebert et al, ; Jadkauskaite et al, ; Raghunath et al, ; Siegenthaler et al, ; Sivandzade, Prasad, Bhalerao, & Cucullo, ; Tonelli, Chio, & Tuveson, ; Vega, Krajisnik, Zhang, & Wondrak, ; Yamamoto, Kensler, & Motohashi, ).…”

Section: Nrf2‐activating Therapeuticsmentioning

confidence: 99%

Epigenetic treatment of dermatologic disorders

Moos

Faller

Glavas

et al. 2019

Drug Development Research

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Healthy skin protects us against a multitude of insults, but injured or maladapted skin can lead to infection, inflammation, or worse. Fortunately, naturally occurring bioactive products, many commonly found in olive oil and other plant and vegetable extracts, have shown utility in treating skin and related diseases as well as conditioning the skin to maintain its healthy function. Powerful agents targeting nuclear regulatory pathways continue to hold promise as new or repurposed therapies for a wide variety of ills and skin conditions. Epigenetic approaches that activate Nrf2 to effect detoxification, redox balance, DNA repair, and mitochondrial function are noteworthy. Some of the disease applications being actively investigated range from eczema and psoriasis to skin cancer and diabetes‐related wound healing to name just a few.

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Transcriptional Regulation by Nrf2

Cited by 1,568 publications

References 198 publications

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

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

Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma

Epigenetic treatment of dermatologic disorders

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