The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation.

By Holly Bryan, Adedamola Olayanju, C. Goldring, B. K. Park. Biochemical Pharmacology, 2013

1,005 citations recorded by the source corpus.

The transcription factor Nrf2 (NF-E2-related factor 2) plays a vital role in maintaining cellular homeostasis, especially upon the exposure of cells to chemical or oxidative stress, through its ability to regulate the basal and inducible expression of a multitude of antioxidant proteins, detoxification enzymes and xenobiotic transporters. In addition, Nrf2 contributes to diverse cellular functions including differentiation, proliferation, inflammation and lipid synthesis and there is an increasing association of aberrant expression and/or function of Nrf2 with pathologies including cancer, neurodegeneration and cardiovascular disease. The activity of Nrf2 is primarily regulated via its interaction with Keap1 (Kelch-like ECH-associated protein 1), which directs the transcription factor for proteasomal degradation. Although it is generally accepted that modification (e.g. chemical adduction, oxidation, nitrosylation or glutathionylation) of one or more critical cysteine residues in Keap1 represents a likely chemico-biological trigger for the activation of Nrf2, unequivocal evidence for such a phenomenon remains elusive. An increasing body of literature has revealed alternative mechanisms of Nrf2 regulation, including phosphorylation of Nrf2 by various protein kinases (PKC, PI3K/Akt, GSK-3β, JNK), interaction with other protein partners (p21, caveolin-1) and epigenetic factors (micro-RNAs -144, -28 and -200a, and promoter methylation). These and other processes are potentially important determinants of Nrf2 activity, and therefore may contribute to the maintenance of cellular homeostasis. Here, we dissect evidence supporting these Keap1-dependent and -independent mechanisms of Nrf2 regulation. Furthermore, we highlight key knowledge gaps in this important field of biology, and suggest how these may be addressed experimentally.

Subfields: Molecular Biology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/87ac8bd8af510cb2ac217be62f7d98bdac0385dc

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Citations in the corpus

The Dual Roles of NRF2 in Cancer. (2016, background): “Indeed, NRF2 redirects glucose and glutamine into anabolic pathways, especially under sustained activation ofphosphatidylinositol-3 kinase (PI3K)–AKT signaling; moreover, gain of NRF2 signaling promotes tumorigenesis through an autoregulatory feedback loop involving miRNA-dependent regulation of PPP”
Combination therapy in combating cancer (2017, background): “Further, Nrf2 heterodimerizes with either MAF (proto-oncogene c-Maf), activating transcription factor (ATF) or AP-1 (activator protein-1 transcription factor) and subsequently binds to a specific promoter region (a cis-acting enhancer sequence (TCAG/CXXXGC), termed the antioxidant response element (”
Glutaminolysis: A Hallmark of Cancer Metabolism. (2017, background): “The PI3K/AKT axis can also activate nuclear factor–like 2 (NRF2), a redox-sensitive transcription factor that regulates redox by multiple mechanisms, including production and regeneration of glutathione (GSH) (43).”
The emerging role of the Nrf2–Keap1 signaling pathway in cancer (2013, background): “Supporting a role for these miRNAs in cancer, aberrant expression of miR-28 and miR-144 has been reported in various cancers, including lymphoma, glioma, and squamous cell carcinoma (Bryan et al. 2012).”