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The Biswal Laboratory

Introduction: NRF2-KEAP1 Pathway

nrf2-keap1

Nrf2 (nuclear factor erythroid 2 related factor 2) 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 in the nucleus and binds to antioxidant response elements (ARE) 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. For further information on the Nrf2 pathway, please visit the Nrf2 entry in the "Transcription Factor Encyclopedia".