83 - Nuclear Factor (Erythroid-Derived 2)-Like-1 (NFE2L1): At the Crossroads of Stress Responses

Abstract

The Antioxidant Response Element (ARE, also known as the Electrophile Response Element (EpRE)) activates gene expression in response to various stresses including oxidative stress, xenobiotic stress and inflammation. The factors that bind to AREs/EpREs include the Nuclear Factor (Erythroid-derived 2)-Like proteins (NFE2L or Nrf) and the small Maf proteins. Nrf is a member of the Cap’n’Collar (CNC) family of basic-region leucine zipper (bZIP) transcription factors (Nrf1, Nrf2 and Nrf3) and activate gene expression from AREs/EpREs found in the promoter and enhancer regions of the genes for antioxidant enzymes, enzymes of xenobiotic metabolism and inflammatory factors. The Nrf proteins also regulate expression of subunits of the proteasome, and in this manner, may autoregulate their own levels. In comparison to Nrf2, there are relatively fewer studies on Nrf1. This may be due to a) their very different mechanisms by which they are regulated, b) the knockout mouse for Nrf2 is completely viable, whereas the knockout mouse for Nrf1 is embryonic lethal and c) their different locations within the cell (Nrf2 is cytosolic, whereas Nrf1 is bound to the endoplasmic reticulum (ER)). Our research focuses on Nrf1 and its responses to various stresses (oxidative stress, hypoxia, ER stress and toxin stresses). Here we show evidence of “cross-talk” between these stresses through effects upon Nrf1 function. Specifically, ER stress impinges upon the response of Nrf1 to other types of stresses. The functional units of Nrf1, and the interacting proteins, that may be involved in the regulation of the response of Nrf1 to multiple stresses will be outlined. The implications of such stress cross-talk, in the response to the individual stresses, will be discussed.