NFE2L Regulation BY Endoplasmic Reticulum Stress

Cell survival requires adaptive responses to transient increases of reactive oxygen species (ROS) during stress. The nuclear factor-erythroid 2-like factors (Nrf1 and Nrf2) and Maf cofactors transactivate genes with antioxidant response elements (ARE) to coordinate distinct metabolic pathways following ROS. Nrf2 predominantly responds to oxidative stress and electrophiles to regulate glutathione biosynthesis, while Nrf1 regulates proteasome induction. This thesis shows nuclear accumulation of the longer forms of Nrf1 (p120- and p95-Nrf1) in response to ER stress mediated by tunicamycin (TUN), thapsigargin (THP), and dithiothreitol (DTT) in HEK293T cells. Nrf2, as opposed to Nrf1, was induced by the oxidative stressor antimycin A (AA) in the absence of BiP induction while both Nrfs accumulated in the nuclei from DTT-mediated redox stress. Cell stress was monitored using the H2DCFDA, MTT and PI assays. These results are the first to indicate Nrf1 responds to ER stress distinctly from Nrf2 that responds to mitochondrial ROS.