Oxidative stress plays an important part in the pathogenesis of a variety of diseases. The ability to mount an efficient response against the continuous threat posed by exogenous and endogenous oxidants is essential for cellular homeostasis and survival. Oxidative stress activates transcription of a variety of antioxidant genes through cis-acting sequence known as antioxidant response element (ARE). Members of the Cap-N-Collar family of transcription factors, including Nrf1 and Nrf2, have been identified that bind ARE. Nrf1 and Nrf2 are expressed in a wide range of tissues and cell types, and both bind the ARE as heterodimers with small-Maf proteins. Numerous studies indicate a pivotal role of Nrf2 in ARE function. Herein, we review data derived from cell-based studies and knockout mice in an attempt to define the role and regulation of Nrf1 in oxidative stress response and other functions.
Background: Nrf1 regulates cellular stress response, but nothing is known about how Nrf1 is regulated. Results: Fbw7 binds Nrf1 to promote its ubiquitination and degradation by the proteasome. Conclusion: Nrf1 expression is regulated by Fbw7. Significance: These findings broaden the understanding of how Nrf1 is regulated and suggest that Fbw7 may regulate cellular stress response by controlling turnover of the Nrf family of proteins.
Nuclear factor E2-related factor-1 (Nrf1) is a basic leucine zipper transcription factor that is known to regulate antioxidant and cytoprotective gene expression. It was recently shown that Nrf1 is regulated by SCF-Fbw7 ubiquitin ligase. However our knowledge of upstream signals that targets Nrf1 for degradation by the UPS is not known. We report here that Nrf1 expression is negatively regulated by glycogen synthase kinase 3 (GSK3) in Fbw7-dependent manner. We show that GSK3 interacts with Nrf1 and phosphorylates the Cdc4 phosphodegron domain (CPD) in Nrf1. Mutation of serine residue in the CPD of Nrf1 to alanine (S350A), blocks Nrf1 from phosphorylation by GSK3, and stabilizes Nrf1. Knockdown of Nrf1 and expression of a constitutively active form of GSK3 results in increased apoptosis in neuronal cells in response to ER stress, while expression of the GSK3 phosphorylation resistant S350A–Nrfl attenuates apoptotic cell death. Together these data suggest that GSK3 regulates Nrf1 expression and cell survival function in response to stress activation.
Oxidative and endoplasmic reticulum (ER) stress play an important role in the pathogenesis of neurodegenerative diseases. Nuclear factor E2‐related factor 1 (Nrf1), a member of the Cap n Collar basic‐leucine zipper family of transcription factor, is highly expressed in neuronal cells, and directs expression of genes encoding antioxidants and proteins that make up the proteasome. We found that glycogen synthase kinase 3 (GSK3), which has been implicated in the causation of neurodegenerative disorders, negatively regulates Nrf1 expression by targeting it for ubiquitination and proteosomal degradation. Nrf1 knockdown neuronal cells are sensitized to ER and oxidative stress‐induced apoptosis. Mutation of GSK3 phosphorylation sites on Nrf1 leads to protein stabilization, and protects against stress‐induced apoptosis. Over expression of kinase dead mutant of GSK3 reduces stress‐mediated apoptosis in the Nrf1 knock down cell line. These studies demonstrate a mechanism by which Nrf1 expression is regulated and how Nrf1 impacts on stress‐mediated apoptosis of neuronal cells.Source of Funding – NIH grant.
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