Jd. Fondell et al., UNLIGANDED THYROID-HORMONE RECEPTOR INHIBITS FORMATION OF A FUNCTIONAL PREINITIATION COMPLEX - IMPLICATIONS FOR ACTIVE REPRESSION, Genes & development, 7(7B), 1993, pp. 1400-1410
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.