The nuclear receptor corepressor deacetylase activating domain is essential for repression by thyroid hormone receptor.
Nuclear receptor corepressor (N-CoR) mediates repression by thyroid hormone receptor (TR) as well as other nuclear hormone receptors and transcription factors. N-CoR contains several repression domains that repress transcription when fused to a heterologous DNA binding domain, but their relative importance in the full-length N-CoR molecule is unknown. Here we addressed this important issue by depleting N-CoR in human cells and replacing it with mutant and wild-type murine N-CoR. Although the N-terminal RD binds transducin beta-like protein 1 (TBL1), TBLR1, and mSin3, deletion of this region did not affect the ability of N-CoR to mediate repression by TR. By contrast, deletion of the deacetylase activating domain (DAD) that binds and activates histone deacetylase 3 dramatically hampered N-CoR's function as a TR corepressor. Introduction of a single amino acid mutation in the DAD similarly disabled the corepressor function of N-CoR. Thus, the DAD domain of N-CoR is singularly essential for repression by TR.
Ishizuka
Takahiro
T
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia 19104-6149, USA.
Lazar
Mitchell A
MA
D000581:Amidohydrolases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017353:Gene Deletion; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry*; D056971:Nuclear Receptor Co-Repressor 1; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000737:chemistry*; D012097:Repressor Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D015293:Transducin
C539127:NCOR1 protein, human; C539128:Ncor1 protein, mouse; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D034741:RNA, Small Interfering; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; C119542:TBL1X protein, human; D000581:Amidohydrolases; D006655:Histone Deacetylases; D015293:Transducin