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Differential Effects of Nuclear Receptor Corepressor (N-CoR) Expression Levels on Retinoic Acid Receptor-Mediated Repression Support the Existence of Dynamically Regulated Corepressor Complexes

Cellular and Molecular Medicine (M.S., A.V., C.K.G.) and, Howard Hughes Medical Institute (T.H., R.M.L., M.G.R.), Graduate Program in Biology (R.M.L.),University of California, San Diego, La Jolla, California 92093-0651,
H. Lee Moffitt Cancer Center and Research Institute (W.Y., E.S.), University of South Florida,Tampa, Florida 33612,Salk Institute for Biology (D.A.P.), La Jolla, California 92037

Thyroid hormone and retinoic acid receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors that stimulate the transcription of target genes in the presence of activating ligands and repress transcription in their absence. Transcriptional repression by the thyroid hormone and retinoic acid receptors has been proposed to be mediated by the nuclear receptor corepressor, N-CoR, or the related factor, SMRT (silencing mediator of retinoic acid and thyroid hormone receptors). Recent studies have suggested that transcriptional repression by N-CoR involves a corepressor complex that also contains 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 in the levels of N-CoR expression, suggesting a relatively strict stoichiometric relationship between N-CoR and other components of the corepressor complex. Consistent with this interpretation, overexpression of several functionally defined domains of N-CoR also relieve repression by nuclear receptors. N-CoR is distributed throughout the nucleus in a nonuniform pattern, and a subpopulation becomes concentrated into several discrete dot structures when highly expressed. RPD3 is also widely distributed throughout the nucleus in a nonuniform pattern. Simultaneous imaging of RPD3 and N-CoR suggest that a subset of each of these proteins colocalize, consistent with the existence of coactivator complexes containing both proteins. In addition, a substantial fraction of both N-CoR and mSin3 A/B appear to be independently distributed. These observations suggest that interactions between RPD3 and Sin3/N-CoR complexes may be dynamically regulated.

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