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Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP Axis

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Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP Axis. / 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.

In: Molecular and Cellular Biology, Vol. 32, No. 17, 2012, p. 3486-99.

Research output: Contribution to journalArticle

Harvard

Rada, P, Rojo, AI, Evrard-Todeschi, N, Innamorato, NG, Cotte, A, Jaworski, T, Tobón-Velasco, JC, Devijver, H, García-Mayoral, MF, Van Leuven, F, Hayes, JD, Bertho, G & Cuadrado, A 2012, 'Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP Axis' Molecular and Cellular Biology, vol 32, no. 17, pp. 3486-99.

APA

Rada, P., Rojo, A. I., Evrard-Todeschi, N., Innamorato, N. G., Cotte, A., Jaworski, T., Tobón-Velasco, J. C., Devijver, H., García-Mayoral, M. F., Van Leuven, F., Hayes, J. D., Bertho, G., & Cuadrado, A. (2012). Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP Axis. Molecular and Cellular Biology, 32(17), 3486-99doi: 10.1128/MCB.00180-12

Vancouver

Rada P, Rojo AI, Evrard-Todeschi N, Innamorato NG, Cotte A, Jaworski T et al. Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP Axis. Molecular and Cellular Biology. 2012;32(17):3486-99.

Author

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 / Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP Axis.

In: Molecular and Cellular Biology, Vol. 32, No. 17, 2012, p. 3486-99.

Research output: Contribution to journalArticle

Bibtex - Download

@article{7f89f40e29fd4aabaf6e2bc705fca82d,
title = "Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP Axis",
author = "Patricia Rada and Rojo, {Ana I.} and Nathalie Evrard-Todeschi and Innamorato, {Nadia G.} and Axelle Cotte and Tomasz Jaworski and Tobón-Velasco, {Julio C.} and Herman Devijver and García-Mayoral, {María Flor} and {Van Leuven}, Fred and Hayes, {John D.} and Gildas Bertho and Antonio Cuadrado",
year = "2012",
volume = "32",
number = "17",
pages = "3486--99",
journal = "Molecular and Cellular Biology",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP Axis

A1 - Rada,Patricia

A1 - Rojo,Ana I.

A1 - Evrard-Todeschi,Nathalie

A1 - Innamorato,Nadia G.

A1 - Cotte,Axelle

A1 - Jaworski,Tomasz

A1 - Tobón-Velasco,Julio C.

A1 - Devijver,Herman

A1 - García-Mayoral,María Flor

A1 - Van Leuven,Fred

A1 - Hayes,John D.

A1 - Bertho,Gildas

A1 - Cuadrado,Antonio

AU - Rada,Patricia

AU - Rojo,Ana I.

AU - Evrard-Todeschi,Nathalie

AU - Innamorato,Nadia G.

AU - Cotte,Axelle

AU - Jaworski,Tomasz

AU - Tobón-Velasco,Julio C.

AU - Devijver,Herman

AU - García-Mayoral,María Flor

AU - Van Leuven,Fred

AU - Hayes,John D.

AU - Bertho,Gildas

AU - Cuadrado,Antonio

PY - 2012

Y1 - 2012

N2 - 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 ß-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 3ß (GSK-3ß) in the sequence DSGISL. Nuclear magnetic resonance studies defined key residues of this phosphosequence involved in docking to the WD40 propeller of ß-TrCP, through electrostatic and hydrophobic interactions. We also identified three arginine residues of ß-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-3ß 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/ß-TrCP axis and its functional relevance in the regulation of Nrf2 by the signaling pathways that impinge on GSK-3.

AB - 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 ß-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 3ß (GSK-3ß) in the sequence DSGISL. Nuclear magnetic resonance studies defined key residues of this phosphosequence involved in docking to the WD40 propeller of ß-TrCP, through electrostatic and hydrophobic interactions. We also identified three arginine residues of ß-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-3ß 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/ß-TrCP axis and its functional relevance in the regulation of Nrf2 by the signaling pathways that impinge on GSK-3.

U2 - 10.1128/MCB.00180-12

DO - 10.1128/MCB.00180-12

M1 - Article

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

IS - 17

VL - 32

SP - 3486

EP - 3499

ER -

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