ALTERATION OF A SINGLE AMINO-ACID RESIDUE IN RETINOIC ACID RECEPTOR CAUSES DOMINANT-NEGATIVE PHENOTYPE

Thyroid hormone receptor (TR) and retinoic acid receptor (RAR) are clo sely related not only in their structures but also in their modes of a ction. TR and RAR share many amino acids in the functionally important DNA binding domain, ligand binding domain, and heterodimeric interfac e. To function, both receptors dimerize with retinoid X receptor, reco gnize their cognate hormone response elements, and then respond to the ligand, leading to the activation of the target genes. Genetic analys is has revealed mutated TRs in thyroid hormone resistance syndrome, wh ich displays autosomal dominant inheritance. Eventually, the mutated T Rs show the dominant-negative phenotype on the wild-type TR. The mutat ions have been observed mostly in conserved amino acids between TR and RAR in the ligand binding domain and produce hormone-insensitive rece ptors. In this report, we demonstrate that the dominant-negative pheno type is transferable to RAR by a single amino acid substitution identi fied in the syndromes of thyroid hormone resistance. The mutated RAR c an suppress the wild-type RAR function, especially at the physiologica l concentration of retinoic acid. Consistently, the mutated RAR is an absolute requirement of intact dimeric and DNA binding capacities for the dominant-negative phenotype, indicating the necessity of the maint enance of a machinery for correct recognition of the targets. Thus, th e hormone-insensitive receptor may be interfering with the access of f unctional receptors to the hormone response elements. The dominant-neg ative RAR will serve as a molecular tool to elucidate physiological ro les of RAR by blocking RAR-mediated signaling pathways.