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Papers In Press, published online ahead of print May 10, 2006
Pathology, University of California Irvine, Irvine, CA 92697-4800
Corresponding Author: jchan{at}uci.edu
Expression of antioxidant and phase 2 xenobiotic metabolizing enzyme genes is regulated through cis-acting sequences known as antioxidant response elements (ARE). Transcriptional activation through the ARE involves members of the Cap ‘n’ Collar (CNC) family of basic leucine zipper proteins including Nrf1 and Nrf2. Nrf2 activity is regulated by Keap1 mediated compartmentalization in the cell. Given the structural similarities between Nrf1 and Nrf2, we sought to investigate whether Nrf1 activity is regulated similarly as Nrf2. Nrf1 also resides normally in the cytoplasm of cells. Cytoplasmic localization however, is independent of Keap1. Colocalization analysis using green fluorescent protein (GFP)-tagged Nrf1 and subcellular fractionation of endogenous Nrf1 and fusion proteins indicate that Nrf1 is primarily a membrane bound protein localized in the endoplasmic reticulum. Membrane targeting is mediated by the N-terminus of the Nrf1 protein that contains a predicted transmembrane domain, and deletion of this domain resulted in a predominantly nuclear localization of Nrf1 that significantly increased the activation of reporter gene expression. Treatment with tunicamycin, an endoplasmic reticulum stress inducer, caused an accumulation of a smaller form of Nrf1 that correlated with detection of Nrf1 in the nucleus by biochemical fractionation and immunofluorescent analysis. These results suggest that Nrf1 is normally targeted to the ER membrane and that ER stress may play a role in modulating Nrf1 function as a transcriptional activator.
J. Biol. Chem, 10.1074/jbc.M602802200
Submitted on March 24, 2006
Revised on May 8, 2006
Accepted on May 10, 2006
Nrf1 is targeted to the ER membrane by a N-terminal transmembrane domain: inhibition of nuclear translocation and transacting function
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