SMRT Derepression by the IκB Kinase α
Open accessAbstract
Understanding how signaling cascades stimulate chromatin-remodeling events through derepression is one of the foremost questions in the transcription field. Here, we demonstrate that NF-kappaB transcription requires IKKalpha to phosphorylate SMRT on chromatin, stimulating the exchange of corepressor for coactivator complexes. IKKalpha-induced phosphorylation coincides with a loss of chromatin-associated SMRT and HDAC3 and with nuclear export of the SMRT corepressor, events required for expression of the NF-kappaB-regulated cIAP-2 and IL-8 genes. Although SMRT derepression corresponds with the recruitment of TBL1/TBLR1, this complex alone is insufficient to relieve repression. Using a nonphosphorylatable SMRT protein, we demonstrate that IKKalpha-induced phosphorylation is required to recruit 14-3-3epsilon and Ubc5 for SMRT derepression. Failure of IKKalpha to stimulate the removal of SMRT from chromatin inhibits the recruitment of NF-kappaB to promoters, blocking transcription and sensitizing cells to apoptosis. Our work provides evidence that IKKalpha orchestrates SMRT derepression, a prerequisite for NF-kappaB transcription and survival.
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Corepressor complexes that remove acetyl groups from Lys310 reduce p65 activity.
“In contrast, deacetylation at Lys310 by corepressor complexes inhibits p65 activity [56, 57].”
From Edible blue-green algae reduce the production of pro-inflammatory cytokines by inhibiting NF-κB pathway in macrophages and splenocytes (2013) · cites this paper as [56]
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- Authors
- Hoberg, J. E., Yeung, F., & Mayo, M. W.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Mayo, Marty W.
- ORCID
- Mayo, Marty W.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2004-10
- Volume
- 16
- Issue
- 2
- Pages
- 245-255
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2603306439
- Cited by
- 220
- References
- 46
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 10 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 6 · 2015: 7 · 2014: 9 · 2013: 20 · 2012: 18
- FWCI
- 8.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k01ca078595-04)
- National Cancer Institute (CA78595, R01CA104397, R01CA095644, CA104397, CA095644, CA110552, F32CA110552)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- SMRT, IKKα, NF-κB transcription, coactivator complexes, HDAC3, 14-3-3ε, cIAP2, interleukin-8, apoptosis, chromatin remodeling
- MeSH terms
- Cell Nucleus, Chromatin, DNA-Binding Proteins, Gene Expression Regulation, Humans, Laminin, Phosphorylation, Repressor Proteins, Serine, Transcription, Genetic, NF-kappa B, Protein Serine-Threonine Kinases, Protein Transport, I-kappa B Kinase, Nuclear Receptor Co-Repressor 2
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