Cited by 699Genomics, phytochemicals, and oxidative stressNF-κB Signaling PathwaysNuclear Receptors and Signaling

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NF-κB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK

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Liu, Guang-Hui, Qu, Jing, Shen, Xun·2008·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

DOI 10.1016/j.bbamcr.2008.01.002

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Abstract

Constitutively activated NF-kappaB occurs in many inflammatory and tumor tissues. Does it interfere with anti-inflammatory or anti-tumor signaling pathway? Here, we report that NF-kappaB p65 subunit repressed the Nrf2-antioxidant response element (ARE) pathway at transcriptional level. In the cells where NF-kappaB and Nrf2 were simultaneously activated, p65 unidirectionally antagonized the transcriptional activity of Nrf2. In the p65-overexpressing cells, the ARE-dependent expression of heme oxygenase-1 was strongly suppressed. However, p65 inhibited the ARE-driven gene transcription in a way that was independent of its own transcriptional activity. Two mechanisms were found to coordinate the p65-mediated repression of ARE: (1) p65 selectively deprives CREB binding protein (CBP) from Nrf2 by competitive interaction with the CH1-KIX domain of CBP, which results in inactivation of Nrf2. The inactivation depends on PKA catalytic subunit-mediated phosphorylation of p65 at S276. (2) p65 promotes recruitment of histone deacetylase 3 (HDAC3), the corepressor, to ARE by facilitating the interaction of HDAC3 with either CBP or MafK, leading to local histone hypoacetylation. This investigation revealed the participation of NF-kappaB p65 in the negative regulation of Nrf2-ARE signaling, and might provide a new insight into a possible role of NF-kappaB in suppressing the expression of anti-inflammatory or anti-tumor genes.

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Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
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Authors: Liu, G.-H., Qu, J., & Shen, X.
Affiliations: Chinese Academy of Sciences (CN)
Corresponding author: Shen, Xun
ORCID: Liu, Guang-Hui
Qu, Jing
Shen, Xun
Venue: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher: Elsevier BV
Published: 2008-05
Volume: 1783
Issue: 5
Pages: 713-727
ISSN: 0167-4889 (ISSN-L)
DOI: 10.1016/j.bbamcr.2008.01.002
OpenAlex: W2113024198
Cited by: 697
References: 77
Citations by year: 2026: 54 · 2025: 45 · 2024: 51 · 2023: 47 · 2022: 68 · 2021: 51 · 2020: 59 · 2019: 59 · 2018: 47 · 2017: 38 · 2016: 32 · 2015: 33 · 2014: 15 · 2013: 28 · 2012: 13
FWCI: 7.82
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1904 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
PubMed (publishedVersion)
Funders: National Natural Science Foundation of China (30330250, 30570462)
Shanghai Municipal Education Commission (E-04010)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords: NF-κB p65, Nrf2, antioxidant response element, CBP, HDAC3, MafK, heme oxygenase-1, transcriptional repression, histone deacetylation, histone hypoacetylation, PKA phosphorylation, corepressor recruitment, anti-inflammatory signaling
MeSH terms: Histone Deacetylase 3, Antioxidants, Cell Line, Gene Expression Regulation, Histone Deacetylases, Humans, Transcription, Genetic, Trans-Activators, NF-kappa B, Response Elements, CREB-Binding Protein, MafK Transcription Factor, NF-E2-Related Factor 2, Transcription Factor RelA

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NF-κB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK

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