Ligand-dependent antagonism by retinoid X receptors of inhibitory thyroid hormone response elements

Area of Science:

• Molecular Endocrinology
• Gene Regulation
• Nuclear Receptors

Background:

• The precise role of retinoid X receptors (RXRs) in regulating gene expression via negative thyroid hormone response elements (nTREs) remains unclear.
• Thyroid hormone receptor (T3R) binding to nTREs typically mediates gene inhibition, but the influence of co-receptors like RXRs is not fully elucidated.

Purpose of the Study:

• To investigate the mechanism by which RXRs modulate T3R activity on nTREs.
• To determine the role of 9-cis retinoic acid (9-cis RA) in RXR-mediated antagonism of thyroid hormone signaling.

Main Methods:

• Utilized reporter gene assays in cell transfection systems.
• Investigated the effects of T3R beta 1, RXR-alpha, and retinoic acid receptor-alpha expression vectors on TSH-beta gene activity.
• Examined the necessity of RXR DNA- and ligand-binding domains for antagonism.

Main Results:

• Demonstrated orientation-specific monomeric T3R binding to a TSH-beta nTRE mediates thyroid hormone inhibition.
• Showed that 9-cis RA significantly reduces thyroid hormone inhibition of the TSH-beta gene, indicating antagonism by endogenous retinoid receptors.
• Confirmed that RXR-alpha, but not retinoic acid receptor-alpha, antagonizes T3R function in the presence of 9-cis RA.
• Found that RXR antagonism and removal of T3R from the nTRE require intact RXR DNA- and ligand-binding domains.

Conclusions:

• Proposed a model where ligand-bound RXR actively removes monomeric T3R from nTREs.
• Established the first evidence of 9-cis RA-dependent antagonism of thyroid hormone inhibition via nTREs.
• Highlighted the crucial role of RXRs in fine-tuning thyroid hormone signaling through nTREs.