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The official symbol for this TF is NFE2L2 (nuclear factor erythroid 2 related factor 2) but this article will refer to it as NRF2, echoing the predominant use of this alias in the literature.
Nrf2 is a basic "cap and collar" leucine zipper transcription factor, which regulates environmental stress response by activating the expression of genes for antioxidants and detoxification enzymes. The Nrf2-directed environmental stress response protects cells against variety of stressors including environmental pollutants such as electrophiles and oxidizing agents, immunotoxicants, and inflammation
Under normal conditions, Nrf2 is bound to Keap1 (Kelch-like erythroid-cell-derived protein with CNC homology [ECH]-associated protein), which anchors it in the cytoplasm and targets it for ubiquitination and proteasome degradation. Upon exposure to stressors, the Nrf2-Keap1 complex dissociates and Nrf2 translocates to the nucleus. This activation involves modification of the Nrf2-Keap1 complex by phosphorylation of Nrf2 and/or covalent binding of inducer molecules to certain cysteine residues in Keap1. Nrf2 heterodimerizes with small Maf proteins (avian musculoaponeurotic fibrosarcoma) in the nucleus and binds to antioxidant response elements (AREs) on target gene promoters.
The list of Nrf2 target genes, which constitute environmental stress response, has been growing since the first transcriptional profile was published by our group in 2001 and it includes pathways for xenobiotic detoxification, antioxidants, anti-inflammatory response, DNA repair, molecular chaperones, and proteasome systems. The degree of expression of these genes involves other transcription factors such as small Mafs and BACHs (brain acyl-CoA hydrolases), which bind to either AREs or Nrf2, or both .
Gene-environment interactions that regulate inflammation and oxidative stress play an important role in determining susceptibility to lung diseases. Past research has focused on understanding the role of Nrf2 in the regulation of environmental stress response and oxidative stress. Studies have shown that Nrf2 may be critically involved in various pulmonary diseases such as chronic obstructive pulmonary disease (COPD), sepsis mediated lung injury, asthma, and cancer .
Recent studies have indicated that suboptimal stress response as a result of decline in Nrf2 in the lung and macrophages is associated with increased oxidative stress and inflammation and worsened COPD in patients . Strategies based on targeting Nrf2 using small molecule approach for intervention of these disorders are being developed .
See Kensler, Wakabayashi, and Biswal review (see Papers tab) for informative figures illustrating these processes.