Similarities and Differences between Two Modes of Antagonism of the Thyroid Hormone Receptor

Title

Similarities and Differences between Two Modes of Antagonism of the Thyroid Hormone Receptor

Creator

Sadana P; Hwang J Y; Attia R R; Arnold L A; Neale G; Guy R K

Publisher

Acs Chemical Biology

Date

2011
2011-10

Description

Thyroid hormone (T3) mediates diverse physiological functions including growth, differentiation, and energy homeostasis through the thyroid hormone receptors (TR). The TR binds DNA at specific recognition sequences in the promoter regions of their target genes known as the thyroid, hormone response elements (TREs). Gene expression at TREs regulated by TRs is mediated by coregulator recruitment to the DNA bound receptor. This TR-coregulator interaction controls transcription of target genes by multiple mechanisms including covalent histone modifications and chromatin remodeling. Our previous studies identified a beta-aminoketone as a potent inhibitor of the TR-coactivator interaction. We describe here the activity of one of these inhibitors in modulating effects of T3 signaling in comparison to an established ligand-competitive inhibitor of TR, NH-3. The beta-aminoketone was found to reverse thyroid hormone induced gene expression by inhibiting coactivator recruitment at target gene promoters, thereby regulating downstream effects of thyroid hormone. While mimicking the downstream effects of NH-3 at the molecular level, the beta-aminoketone affects only a subset of the thyroid responsive signaling network. Thus antagonists directed to the coregulator binding site have distinct pharmacological properties relative to ligand-based antagonists and may provide complementary activity in vivo.

Subject

androgen receptor; Biochemistry & Molecular Biology; coactivator binding; estrogen receptor; gene-expression; growth-hormone; hepatoma-cell line; hepg2; liver; nuclear receptor; small-molecule inhibitors

Identifier

Format

Journal Article

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

1096-1106

Issue

10

Volume

6

Citation

Sadana P; Hwang J Y; Attia R R; Arnold L A; Neale G; Guy R K, “Similarities and Differences between Two Modes of Antagonism of the Thyroid Hormone Receptor,” NEOMED Bibliography Database, accessed August 1, 2021, https://neomed.omeka.net/items/show/6987.

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