Thyroid hormone (T3) mediates its action through thyroid hormone receptors (TRs), which are transcription factors that bind to specific thyroid hormone response elements (TREs) in the regulatory regions of T3 responsive genes. TRs are members of the nuclear hormone receptor superfamily of transcription factors, characterized by shared structural elements and mechanisms of action. TRs can bind to TREs as monomers, homodimers and heterodimers with the retinoid X receptor (RXR), another member of the nuclear hormone receptor superfamily. Much of the published literature suggests that most naturally occurring TREs serve as binding sites for the TR/RXR heterodimer, however the requirement for RXR in T3 gene regulation is unknown. Understanding the role of RXR in T3 action may provide insight into how different tissues can regulate T3 responsive genes in the setting of relatively constant T3 exposure. For example, in genes requiring RXR for T3 responsiveness, the magnitude of T3 response may be dependent on the availability of RXR or RXR ligand. Other T3 regulated genes would be independent of RXR. It may also be that co-activator requirements are different for TR homodimers when compared to TR/RXR heterodimers. This study will undertake to define the RXR requirement by using a novel dominant negative inhibitor of RXR function.
