UNLIGANDED THYROID-HORMONE RECEPTOR INHIBITS FORMATION OF A FUNCTIONAL PREINITIATION COMPLEX - IMPLICATIONS FOR ACTIVE REPRESSION

The thyroid hormone receptor (TR) belongs to the steroid/nuclear recep tor superfamily of ligand-inducible transcription factors. Numerous st udies using transient transfection assays have demonstrated that in th e absence of thyroid hormone (T3), unliganded TR acts as a constitutiv e repressor of transcription on genes bearing TR-response elements. We examined the molecular mechanism of TR repression in vitro using both HeLa nuclear extracts and purified basal factors. Here, we show that unliganded TR is an active transcriptional repressor, distinct from pa ssive repressors that compete with activators for DNA binding. Repress ion by TR can be relieved by adding the T3 analog triiodothyroactic ac id, suggesting that liganded TR undergoes a conformational change that masks or disrupts the repressor function. Repression by TR is mediate d through the basal transcription machinery and can occur independentl y of previously characterized TATA-binding protein-associated cofactor s thought to be involved in either basal repression or activator-depen dent transcription. TR inhibits transcription at an early step during preinitiation complex (PIC) assembly, as preassembled PICs are refract ory to the inhibitory effects of TR.