TAU-4 TAU-C/AF-2 OF THE THYROID-HORMONE RECEPTOR RELIEVES SILENCING OF THE RETINOIC ACID RECEPTOR SILENCER CORE INDEPENDENT OF BOTH TAU-4 ACTIVATION FUNCTION AND FULL DISSOCIATION OF COREPRESSORS/

Members of the thyroid hormone (TR)-retinoic acid receptor (RAR) subfa mily of nuclear hormone receptors silence gene expression in the absen ce of hormone, Addition of cognate ligands leads to dissociation of co repressors, association of coactivators, and transcriptional activatio n, Here, we used the hRAR alpha silencer core, which encompasses the l igand binding domain, including receptor regions D and E of RAR alpha without the activation function called tau 4/tau c/AF-2 and without th e F region, to analyze the mechanisms by which transcriptional silenci ng is relieved, Although the RAR silencer core is able to bind ligand, it acts as a constitutive transcriptional silencer, We have fused var ious small activation domains to the C terminus of the silencer core a nd analyzed hormone-dependent changes in receptor function. We show th at nine amino acids derived from the hTR beta are sufficient to transf orm the RAR silencer core into a hormone-dependent activator, Lengthen ing the linker between the silencer core and these nine amino acids is not critical for mediating ligand-induced relief of silencing and act ivation. In addition, we show that a transactivation function at the C terminus is not required for relief of silencing by the hormone, but it is required for transcriptional activation, Furthermore, we created functional silencer fusions which lose their repressive function upon addition of hormone, although the corepressors SMRT and N-CoR remain attached to the receptor.