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Molecular Endocrinology 16 (7): 1482-1491
Copyright © 2002 by The Endocrine Society

Direct Interactions between Corepressors and Coactivators Permit the Integration of Nuclear Receptor-Mediated Repression and Activation

Xiaolin Li1, Erin A. Kimbrel1, Daniel J. Kenan and Donald P. MCDonnell

Departments of Pharmacology and Cancer Biology (X.L., E.A.K., D.P.M.) and Pathology (D.J.K.), Duke University Medical Center, Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Dr. Donald P. McDonnell, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710. E-mail: mcdon016{at}acpub.duke.edu.

The unliganded thyroid hormone receptor ß (TRß) represses the basal transcriptional activity of target genes, in part through interactions with the nuclear receptor corepressor (N-CoR). In this study we have identified a rather unexpected interaction between N-CoR and the nuclear receptor coactivator ACTR. We have demonstrated in vitro and in intact cells that N-CoR directly associates with ACTR and that the interaction surfaces on N-CoR and ACTR are distinct from those required for TR binding. The significance of this finding was demonstrated by showing that N-CoR facilitates an interaction between unliganded-TRß and ACTR. One possible consequence of the formation of the trimeric complex of N-CoR/ACTR/unliganded-TR is that N-CoR may raise the local concentration of ACTR at target gene promoters. In support of this hypothesis it was demonstrated that the presence of N-CoR can enhance TRß-mediated transcriptional activation. It is proposed, therefore, that TRß- mediated activation and repression are integrally linked in a manner that is not predicted by the current models of nuclear receptor action.




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