Direct interactions between corepressors and coactivators permit the integration of nuclear receptor-mediated repression and activation.
The unliganded thyroid hormone receptor beta (TRbeta) 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-TRbeta 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 TRbeta-mediated transcriptional activation. It is proposed, therefore, that TRbeta- mediated activation and repression are integrally linked in a manner that is not predicted by the current models of nuclear receptor action.
Li
Xiaolin
X
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Kimbrel
Erin A
EA
Kenan
Daniel J
DJ
McDonnell
Donald P
DP
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002478:Cells, Cultured; D051548:Histone Acetyltransferases; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D056920:Nuclear Receptor Coactivator 1; D051958:Nuclear Receptor Coactivator 2; D011401:Promoter Regions, Genetic; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D051958:Nuclear Receptor Coactivator 2; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1