Abstract
Nuclear factor E2-related factor 1 (Nrf1) is a basic leucine zipper transcription factor that plays an important role in the activation of cytoprotective genes through the antioxidant response elements. The previously characterized long isoform of Nrf1 (Nrf1a) is targeted to the endoplasmic reticulum and accumulates in the nucleus in response to activating signals. Here we characterized a novel Nrf1 protein isoform (Nrf1b) generated through an alternative promoter and first exon that lacks the ER targeting domain of Nrf1a. The 5′-flanking region of Nrf1b directed high levels of luciferase reporter expression in cells. RT-PCR and Western blotting showed Nrf1b is widely expressed in various cell lines and mouse tissues. Immunoblot analysis of subcellular fractions and imaging of green fluorescence protein (GFP)-tagged Nrf1b demonstrate Nrf1b is constitutively localized to the nucleus. Nrf1b can activate GAL4-dependent transcription when fused to the heterologous GAL4 DNA-binding domain. Gel-shift and coimmunoprecipitation experiments demonstrate that Nrf1b forms a complex with MafG, and expression of Nrf1b activates the expression of antioxidant response element containing reporters and genes in cells. These results suggest Nrf1b is targeted to the nucleus where it activates ARE-driven genes and may play a role in modulating antioxidant response elements.
Highlights
Nuclear factor erythroid-derived 2-related factor 1 (Nrf1) is a member of the Cap ‘n’Collar (CNC) family of transcription factors that includes 3 closely related members, Nrf2, Nrf3, and p45NFE2 [1,2,3,4]
Nrf1 is a member of the CNC basic leucine zipper family of transcription factors that play important roles in gene regulation and cellular development
Nrf1b transcript is derived from an alternative promoter site in the Nrf1 gene and encodes a structurally different protein than Nrf1a
Summary
Nuclear factor erythroid-derived 2-related factor 1 (Nrf1) is a member of the Cap ‘n’Collar (CNC) family of transcription factors that includes 3 closely related members, Nrf, Nrf, and p45NFE2 [1,2,3,4]. Nrf knock-out mice demonstrated the importance of Nrf in conferring protection from oxidative stress-related diseases in various organs, while Nrf proved to be vital in mouse embryonic development [6]. Despite the similar functions of Nrf and Nrf in maintaining cellular homeostasis and protecting against oxidative damage, Nrf has been suggested to play a distinct role in regulating AREdriven genes. Studies of liver-specific and brainspecific Nrf knockout mice have elucidated Nrf1’s importance in preventing non-alcoholic steatohepatitis and neurodegeneration, respectively [12,13]. Metallothionein genes (MT1 and MT2) have been shown to be activated exclusively by Nrf1 [14]
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