ITEM METADATA RECORD
Title: Structural and Functional Characterization of Nrf2 Degradation by the Glycogen Synthase Kinase 3/β-TrCP Axis
Authors: Rada, Patricia ×
Rojo, Ana I
Evrard-Todeschi, Nathalie
Innamorato, Nadia G
Cotte, Axelle
Jaworski, Tomasz
Tobón-Velasco, Julio C
Devijver, Herman
García-Mayoral, María Flor
Van Leuven, Fred
Hayes, John D
Bertho, Gildas
Cuadrado, Antonio #
Issue Date: Sep-2012
Publisher: American Society for Microbiology (ASM)
Series Title: Molecular and Cellular Biology vol:32 issue:17 pages:3486-3499
Abstract: The transcription factor NF-E2-related factor 2 (Nrf2) is a master regulator of a genetic program, termed the phase 2 response, that controls redox homeostasis and participates in multiple aspects of physiology and pathology. Nrf2 protein stability is regulated by two E3 ubiquitin ligase adaptors, Keap1 and β-TrCP, the latter of which was only recently reported. Here, two-dimensional (2D) gel electrophoresis and site-directed mutagenesis allowed us to identify two serines of Nrf2 that are phosphorylated by glycogen synthase kinase 3β (GSK-3β) in the sequence DSGISL. Nuclear magnetic resonance studies defined key residues of this phosphosequence involved in docking to the WD40 propeller of β-TrCP, through electrostatic and hydrophobic interactions. We also identified three arginine residues of β-TrCP that participate in Nrf2 docking. Intraperitoneal injection of the GSK-3 inhibitor SB216763 led to increased Nrf2 and heme oxygenase-1 levels in liver and hippocampus. Moreover, mice with hippocampal absence of GSK-3β exhibited increased levels of Nrf2 and phase 2 gene products, reduced glutathione, and decreased levels of carbonylated proteins and malondialdehyde. This study establishes the structural parameters of the interaction of Nrf2 with the GSK-3/β-TrCP axis and its functional relevance in the regulation of Nrf2 by the signaling pathways that impinge on GSK-3.
URI: 
ISSN: 0270-7306
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Experimental Genetics and Transgenesis (-)
× corresponding author
# (joint) last author

Files in This Item:

There are no files associated with this item.

 


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science