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p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription

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p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. / Jain, Ashish; Lamark, Trond; Sjottem, Eva; Larsen, Kenneth Bowitz; Awuh, Jane Atesoh; Overvatn, Aud; McMahon, Michael; Hayes, John D.; Johansen, Terje.

In: Journal of Biological Chemistry, Vol. 285, No. 29, 16.07.2010, p. 22576-22591.

Research output: Contribution to journalArticle

Harvard

Jain, A, Lamark, T, Sjottem, E, Larsen, KB, Awuh, JA, Overvatn, A, McMahon, M, Hayes, JD & Johansen, T 2010, 'p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription' Journal of Biological Chemistry, vol 285, no. 29, pp. 22576-22591.

APA

Jain, A., Lamark, T., Sjottem, E., Larsen, K. B., Awuh, J. A., Overvatn, A., McMahon, M., Hayes, J. D., & Johansen, T. (2010). p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. Journal of Biological Chemistry, 285(29), 22576-22591doi: 10.1074/jbc.M110.118976

Vancouver

Jain A, Lamark T, Sjottem E, Larsen KB, Awuh JA, Overvatn A et al. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. Journal of Biological Chemistry. 2010 Jul 16;285(29):22576-22591.

Author

Jain, Ashish; Lamark, Trond; Sjottem, Eva; Larsen, Kenneth Bowitz; Awuh, Jane Atesoh; Overvatn, Aud; McMahon, Michael; Hayes, John D.; Johansen, Terje / p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription.

In: Journal of Biological Chemistry, Vol. 285, No. 29, 16.07.2010, p. 22576-22591.

Research output: Contribution to journalArticle

Bibtex - Download

@article{83c8b14f9b424b70adab0b3ab0dfcd5d,
title = "p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription",
author = "Ashish Jain and Trond Lamark and Eva Sjottem and Larsen, {Kenneth Bowitz} and Awuh, {Jane Atesoh} and Aud Overvatn and Michael McMahon and Hayes, {John D.} and Terje Johansen",
year = "2010",
volume = "285",
number = "29",
pages = "22576--22591",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription

A1 - Jain,Ashish

A1 - Lamark,Trond

A1 - Sjottem,Eva

A1 - Larsen,Kenneth Bowitz

A1 - Awuh,Jane Atesoh

A1 - Overvatn,Aud

A1 - McMahon,Michael

A1 - Hayes,John D.

A1 - Johansen,Terje

AU - Jain,Ashish

AU - Lamark,Trond

AU - Sjottem,Eva

AU - Larsen,Kenneth Bowitz

AU - Awuh,Jane Atesoh

AU - Overvatn,Aud

AU - McMahon,Michael

AU - Hayes,John D.

AU - Johansen,Terje

PY - 2010/7/16

Y1 - 2010/7/16

N2 - The p62/SQSTM1 (sequestosome 1) protein, which acts as a cargo receptor for autophagic degradation of ubiquitinated targets, is up-regulated by various stressors. Induction of the p62 gene by oxidative stress is mediated by NF-E2-related factor 2 (NRF2) and, at the same time, p62 protein contributes to the activation of NRF2, but hitherto the mechanisms involved were not known. Herein, we have mapped an antioxidant response element (ARE) in the p62 promoter that is responsible for its induction by oxidative stress via NRF2. Chromatin immunoprecipitation and gel mobility-shift assays verified that NRF2 binds to this cis-element in vivo and in vitro. Also, p62 docks directly onto the Kelch-repeat domain of Kelch-like ECH-associated protein 1 (KEAP1), via a motif designated the KEAP1 interacting region (KIR), thereby blocking binding between KEAP1 and NRF2 that leads to ubiquitylation and degradation of the transcription factor. The KIR motif in p62 is located immediately C-terminal to the LC3-interacting region (LIR) and resembles the ETGE motif utilized by NRF2 for its interaction with KEAP1. KIR is required for p62 to stabilize NRF2, and inhibition of KEAP1 by p62 occurs from a cytoplasmic location within the cell. The LIR and KIR motifs cannot be engaged simultaneously by LC3 and KEAP1, but because p62 is polymeric the interaction between KEAP1 and p62 leads to accumulation of KEAP1 in p62 bodies, which is followed by autophagic degradation of KEAP1. Our data explain how p62 contributes to activation of NRF2 target genes in response to oxidative stress through creating a positive feedback loop.

AB - The p62/SQSTM1 (sequestosome 1) protein, which acts as a cargo receptor for autophagic degradation of ubiquitinated targets, is up-regulated by various stressors. Induction of the p62 gene by oxidative stress is mediated by NF-E2-related factor 2 (NRF2) and, at the same time, p62 protein contributes to the activation of NRF2, but hitherto the mechanisms involved were not known. Herein, we have mapped an antioxidant response element (ARE) in the p62 promoter that is responsible for its induction by oxidative stress via NRF2. Chromatin immunoprecipitation and gel mobility-shift assays verified that NRF2 binds to this cis-element in vivo and in vitro. Also, p62 docks directly onto the Kelch-repeat domain of Kelch-like ECH-associated protein 1 (KEAP1), via a motif designated the KEAP1 interacting region (KIR), thereby blocking binding between KEAP1 and NRF2 that leads to ubiquitylation and degradation of the transcription factor. The KIR motif in p62 is located immediately C-terminal to the LC3-interacting region (LIR) and resembles the ETGE motif utilized by NRF2 for its interaction with KEAP1. KIR is required for p62 to stabilize NRF2, and inhibition of KEAP1 by p62 occurs from a cytoplasmic location within the cell. The LIR and KIR motifs cannot be engaged simultaneously by LC3 and KEAP1, but because p62 is polymeric the interaction between KEAP1 and p62 leads to accumulation of KEAP1 in p62 bodies, which is followed by autophagic degradation of KEAP1. Our data explain how p62 contributes to activation of NRF2 target genes in response to oxidative stress through creating a positive feedback loop.

KW - PROTEIN-KINASE-C

KW - PHOSPHOTYROSINE-INDEPENDENT LIGAND

KW - CUL3-BASED E3 LIGASE

KW - KAPPA-B ACTIVATION

KW - OXIDATIVE STRESS

KW - SELECTIVE AUTOPHAGY

KW - PROTEASOMAL DEGRADATION

KW - NEURITE OUTGROWTH

KW - SIGNALING PATHWAY

KW - BINDING PROTEIN

U2 - 10.1074/jbc.M110.118976

DO - 10.1074/jbc.M110.118976

M1 - Article

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 29

VL - 285

SP - 22576

EP - 22591

ER -

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