Gerhart Graupner

Formation of retinoid X receptor homodimers leads to repression of T3 response : hormonal cross talk by ligand-induced squelching

Thyroid hormone receptors (TRs) form heterodimers with retinoid X receptors (RXRs). Heterodimerization is required for efficient TR DNA binding to most response elements and transcriptional activation by thyroid hormone. RXRs also function as auxiliary proteins for several other receptors. In addition, RXR alpha can be induced by specific ligands to form homodimers. Here we report that RXR-specific retinoids that induce RXR homodimers are effective repressors of the T3 response. We provide evidence that this repression by RXR-specific ligands occurs by sequestering of RXR from TR-RXR heterodimers into RXR homodimers. This ligand-induced squelching may represent an important mechanism by which RXR-specific retinoids and 9-cis retinoic acid mediate hormonal cross talk among a subfamily of nuclear receptors activated by structurally unrelated ligands.

Nuclear retinoic acid receptors: cloning, analysis, and function.

Publisher Summary This chapter describes rapid and sensitive methods procedures for the probing, cloning, and analysis of nuclear retinoic acid receptors and their ligands. The procedures can be easily adapted for the general analysis of other proteins. Conventional cDNA cloning approaches are time-consuming and require a multitude of skills; this chapter presents an easy to follow polymerase chain reaction (PCR) procedure for the isolation of retinoic acid receptor (RAR) cDNA that can be accomplished within a few days. The chapter discusses two analysis systems can be used to determine quickly the overall integrity of the PCR clone. One is the in vitro transcription/translation assay. The second analysis system evaluates the functional integrity of the encoded receptor protein in the transient transfection system. The chapter describes an efficient procedure that allowed comparing the gene activation capacity of a large number of individual synthetic retinoids. This system will be extremely useful for the evaluation of optimal, receptor-specific agonists and antagonists.