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GSK3 negatively regulates stress response mediated by transcription factor Nrf1, resulting in increased neuronal apoptosis and neurodegeneration
Author(s) -
Biswas Madhurima,
Chan Jefferson Y.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb479
Subject(s) - nrf1 , transcription factor , microbiology and biotechnology , unfolded protein response , endoplasmic reticulum , biology , neurodegeneration , gsk 3 , gene knockdown , apoptosis , kinase , chemistry , biochemistry , gene , medicine , disease
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.