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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 16, 2013
Negative regulation by thyroid hormone receptor requires an intact coactivator-binding surface
Tania M Ortiga-Carvalho1, Nobuyuki Shibusawa, Amisra Nikrodhanond
1Department of Medicine and Committee on Molecular Metabolism and Nutrition, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois, USA.
The Journal of Clinical Investigation
|August 16, 2005
Summary
Thyroid hormone (TH) action relies on thyroid hormone receptors (TRs). This study reveals the TR-beta activation function-2 domain is crucial for both activating and paradoxically inhibiting TH
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Thyroid hormone (TH) exerts its effects via thyroid hormone receptors (TRs), nuclear hormone receptors that interact with coregulatory proteins.
- TR activity is modulated by corepressors (CoRs) and coactivators (CoAs), with TH stimulation typically involving CoA recruitment and CoR dissociation.
Purpose of the Study:
- To investigate the in vivo physiological role of coactivator proteins bound to TRs.
- To elucidate the function of the TR-beta activation function-2 (AF-2) domain in thyroid hormone regulation.
Main Methods:
- Gene targeting was used to create a mutation (E457A) in the TR-beta AF-2 domain, abolishing CoA recruitment in vitro while maintaining T3 binding and CoR interactions.
- Homozygous E457A mutant mice were analyzed for thyroid hormone regulation and hypothalamic-pituitary-thyroid axis function.
Main Results:
- Homozygous E457A mice exhibited reduced TH-stimulated gene expression.
- These mice showed paradoxical abnormalities, including elevated serum thyroxine, T3, and TSH levels, and failed suppression of TSH by L-T3 treatment.
Conclusions:
- The TR-beta AF-2 domain is essential for both positive and negative regulation of the hypothalamic-pituitary-thyroid axis by thyroid hormone in vivo.
- This finding highlights a critical role for coactivator recruitment in the complete spectrum of thyroid hormone action.
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