The Nuclear Receptor Corepressor Deacetylase Activating Domain Is Essential for Repression by Thyroid Hormone Receptor
Open accessAbstract
Nuclear receptor corepressor (N-CoR) mediates repression by thyroid hormone receptor (TR) as well as other nuclear hormone receptors and transcription factors. N-CoR contains several repression domains that repress transcription when fused to a heterologous DNA binding domain, but their relative importance in the full-length N-CoR molecule is unknown. Here we addressed this important issue by depleting N-CoR in human cells and replacing it with mutant and wild-type murine N-CoR. Although the N-terminal RD binds transducin beta-like protein 1 (TBL1), TBLR1, and mSin3, deletion of this region did not affect the ability of N-CoR to mediate repression by TR. By contrast, deletion of the deacetylase activating domain (DAD) that binds and activates histone deacetylase 3 dramatically hampered N-CoR's function as a TR corepressor. Introduction of a single amino acid mutation in the DAD similarly disabled the corepressor function of N-CoR. Thus, the DAD domain of N-CoR is singularly essential for repression by TR.
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Recruitment of HDAC3 to the DAD is essential for repression by certain nuclear receptors and for the maintenance of normal circadian physiology.
“Recruitment of HDAC3 to the DAD is essential for repression by certain nuclear receptors and for the maintenance of normal circadian physiology27-29.”
From Structure of Hdac3 Bound to Co-Repressor and Inositol Tetraphosphate (2012) · cites this paper as [28]
The Discussion reports that the DAD is required for N-CoR to interact with HDAC3 in cells and is essential for repression by the thyroid hormone receptor (p. 1448). The paper does not address maintenance of normal circadian physiology, and its repression experiments concern the thyroid hormone receptor rather than other nuclear receptors. (LLM, conf=0.88)
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References 50 · Cited by 50
- Authors
- Ishizuka, T., & Lazar, M. A.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Lazar, Mitchell A.
- ORCID
- Lazar, Mitchell A.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2005-06
- Volume
- 19
- Issue
- 6
- Pages
- 1443-1451
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2159178673
- Cited by
- 50
- References
- 50
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 1 · 2022: 2 · 2021: 3 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 5 · 2013: 2 · 2012: 4
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania
- National Institute of Diabetes and Digestive and Kidney Diseases (U19 DK062034, R01DK043806)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- nuclear receptor corepressor, thyroid hormone receptor, transcriptional repression, HDAC3
- MeSH terms
- Amidohydrolases, Amino Acid Sequence, Animals, Cell Line, Histone Deacetylases, Humans, Molecular Sequence Data, Mutation, Nuclear Proteins, Plasmids, Receptors, Thyroid Hormone, Repressor Proteins, Transcription, Genetic, Immunoblotting, Transducin, Gene Deletion, Point Mutation, Sequence Homology, Amino Acid, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering, Immunoprecipitation, Mice, Nuclear Receptor Co-Repressor 1
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