title: Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) and inhibits pro-survival function of Nrf1.
abstract: 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-Nrf1 attenuates apoptotic cell death. Together these data suggest that GSK3 regulates Nrf1 expression and cell survival function in response to stress activation.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of California, Irvine, D440 Medical Science 1, Irvine, CA 92697, USA.
authors.forename: Madhurima
authors.initials: M
authors.lastname: Biswas
authors.affiliation: Department of Laboratory Medicine and Pathology, University of California, Irvine, D440 Medical Science 1, Irvine, CA 92697, USA.
authors.forename: Erick K
authors.initials: EK
authors.lastname: Kwong
authors.affiliation: Department of Laboratory Medicine and Pathology, University of California, Irvine, D440 Medical Science 1, Irvine, CA 92697, USA.
authors.forename: Eujean
authors.initials: E
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine and Pathology, University of California, Irvine, D440 Medical Science 1, Irvine, CA 92697, USA.
authors.forename: Parminder
authors.initials: P
authors.lastname: Nagra
authors.affiliation: Department of Laboratory Medicine and Pathology, University of California, Irvine, D440 Medical Science 1, Irvine, CA 92697, USA. Electronic address: jchan@uci.edu.
authors.forename: Jefferson Y
authors.initials: JY
authors.lastname: Chan
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D044783:F-Box Proteins / Q000378:metabolism / Q000502:physiology; D000073979:F-Box-WD Repeat-Containing Protein 7; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D051266:Nuclear Respiratory Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D059748:Proteolysis; D013312:Stress, Physiological / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D044767:Ubiquitin-Protein Ligases; D038362:Glycogen Synthase Kinase 3
keywords: ARE; CNC-BZIP; CNC-bZIP; CPD; Cap ‘n’ Collar-type basic leucine zipper; Cdc4 phosphodegron domain; ER; Fbw7; GSK3; Nrf1; Nuclear factor E2-related factor-1; SCF; Skp1–Cul1–F-box; Stress response; Transcription factor; UPS; antioxidant response element; endoplasmic reticulum; glycogen synthase kinase 3; nuclear factor E2-related factor-1; ubiquitin proteasome system