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Cyclin D1 Is a Ligand-independent Co-repressor for Thyroid Hormone Receptors
Huei-Min Lin1, Li Zhao, Sheue-Yann Cheng
1Gene Regulation Section, Laboratory of Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892-4264, USA.
Abstract:
Thyroid hormone receptors (TRs) are critical regulators of growth, differentiation, and homeostasis. TRs function by regulating the expression of thyroid hormone (T3) target genes in both ligand-dependent and -independent pathways. Distinct classes of co-regulatory proteins modulate these two pathways. We show here a novel role of cyclin D1 as a T3-independent co-repressor for TRs. Cyclin D1 interacted with TR in vitro and in cells in a ligand-independent manner. Cyclin D1 acted to repress both the silencing activity of the unliganded TR and the transcriptional activity of the liganded TR. The repression was not due to the inhibition of the binding of TR to the thyroid hormone response element but by serving as a ligand-independent bridging factor to selectively recruit HDAC3 to form ternary complexes. The repression was augmented by increasing expression of HDAC3 but not by HDAC1 and was alleviated by trichostatin A. Thus, cyclin D1 is a novel ligand-independent co-repressor that opens a new paradigm to understand the molecular basis of the silencing action of TR.
Insights
Cyclin D1 acts as a novel co-repressor for thyroid hormone receptors (TRs), independent of hormone binding. This finding reveals a new mechanism for TR gene silencing and regulation.
Area of Science:
- Molecular Endocrinology
- Gene Regulation
- Cellular Signaling
Background:
- Thyroid hormone receptors (TRs) are crucial for development and metabolism.
- TRs regulate gene expression via ligand-dependent and -independent pathways.
- Co-regulatory proteins modulate TR activity.
Purpose of the Study:
- To investigate the novel role of cyclin D1 in thyroid hormone receptor (TR) function.
- To elucidate the mechanism by which cyclin D1 affects TR activity.
Main Methods:
- In vitro and cellular interaction studies between cyclin D1 and TR.
- Assays to assess TR binding to thyroid hormone response elements.
- Analysis of co-repressor recruitment, specifically HDAC3 and HDAC1.
- Gene expression analysis modulated by trichostatin A.
Main Results:
- Cyclin D1 directly interacts with TR in a ligand-independent manner.
- Cyclin D1 represses both unliganded and liganded TR activity.
- Repression occurs through recruitment of HDAC3, not by inhibiting TR DNA binding.
- HDAC3 overexpression enhances repression, while HDAC1 does not.
Conclusions:
- Cyclin D1 functions as a novel, ligand-independent co-repressor for TRs.
- Cyclin D1 facilitates TR-mediated gene silencing by recruiting HDAC3.
- This discovery offers new insights into the molecular mechanisms of TR action.