DIFFERENTIAL-EFFECTS OF NUCLEAR RECEPTOR COREPRESSOR (N-COR) EXPRESSION LEVELS ON RETINOIC ACID RECEPTOR-MEDIATED REPRESSION SUPPORT THE EXISTENCE OF DYNAMICALLY REGULATED COREPRESSOR COMPLEXES

Thyroid hormone and retinoic acid receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors that s timulate the transcription of target genes in the presence of activati ng ligands and repress transcription in their absence. Transcriptional repression by the thyroid hormone and retinoic acid receptors has bee n proposed to be mediated by the nuclear receptor corepressor, N-CoR, or the related factor, SMRT (silencing mediator of retinoic acid and t hyroid hormone receptors). Recent studies have suggested that transcri ptional repression by N-CoR involves a corepressor complex that also c ontains mSin3A/B and the histone deacetylase, RPD3. In this manuscript , we demonstrate that transcriptional repression by the retinoic acid receptor can be either positively or negatively regulated by changes i n the levels of N-CoR expression, suggesting a relatively strict stoic hiometric relationship between N-CoR and other components of the corep ressor complex. Consistent with this interpretation, overexpression of several functionally defined domains of N-CoR also relieve repression by nuclear receptors. N-CoR is distributed and a subpopulation become s concentrated into several discrete dot structures when highly expres sed. RPD3 is also widely distributed throughout the nucleus in a nonun iform pattern. Simultaneous imaging of RPD3 and N-CoR suggest that a s ubset of each of these proteins colocalize, consistent with the existe nce of coactivator complexes containing both proteins. In addition, a substantial fraction of both N-CoR and mSin3 A/B appear to be independ ently distributed. These observations suggest that interactions betwee n RPD3 and Sin3/N-CoR complexes may be dynamically regulated.