A Corepressor/Coactivator Exchange Complex Required for Transcriptional Activation by Nuclear Receptors and Other Regulated Transcription Factors

• Published in: Cell 2004-02, Vol.116 (4), p.511-526
• Main Authors: Perissi, Valentina, Aggarwal, Aneel, Glass, Christopher K, Rose, David W, Rosenfeld, Michael G
• Format: Article
• Language: English
• Subjects: Adipocytes - cytology; Animals; Cell Differentiation; Cell Nucleus - metabolism; Cells, Cultured; Cysteine Endopeptidases - metabolism; Embryo, Mammalian - cytology; Endothelium, Vascular - cytology; Gene Deletion; Genetic Vectors; Ligands; Mice; Microscopy, Fluorescence; Models, Biological; Models, Genetic; Multienzyme Complexes - metabolism; N-CoR protein; Neurons - cytology; NF-kappa B - metabolism; Nuclear Proteins - metabolism; Precipitin Tests; Proteasome Endopeptidase Complex; Protein Binding; Proto-Oncogene Proteins c-jun - metabolism; Receptors, Cytoplasmic and Nuclear - metabolism; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA - chemistry; Signal Transduction; SMRT protein; Stem Cells - metabolism; TBL1 gene; TBLR1 gene; Transcription Factors - metabolism; Transcriptional Activation; Transducin - metabolism; Ubiquitin - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(04)00133-3

The mechanisms that control the precisely regulated switch from gene repression to gene activation represent a central question in mammalian development. Here, we report that transcriptional activation mediated by liganded nuclear receptors unexpectedly requires the actions of two highly related F box/WD-40-containing factors, TBL1 and TBLR1, initially identified as components of an N-CoR corepressor complex. TBL1/TBLR1 serve as specific adaptors for the recruitment of the ubiquitin conjugating/19S proteasome complex, with TBLR1 selectively serving to mediate a required exchange of the nuclear receptor corepressors, N-CoR and SMRT, for coactivators upon ligand binding. Tbl1 gene deletion in embryonic stem cells severely impairs PPARγ-induced adipogenic differentiation, indicating that TBL1 function is also biologically indispensable for specific nuclear receptor-mediated gene activation events. The role of TBLR1 and TBL1 in cofactor exchange appears to also operate for c-Jun and NFκB and is therefore likely to be prototypic of similar mechanisms for other signal-dependent transcription factors.