A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors.

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 PPARgamma-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 NFkappaB and is therefore likely to be prototypic of similar mechanisms for other signal-dependent transcription factors.
Mesh Terms:
Adipocytes, Animals, Cell Differentiation, Cell Nucleus, Cells, Cultured, Cysteine Endopeptidases, Embryo, Mammalian, Endothelium, Vascular, Gene Deletion, Genetic Vectors, Ligands, Mice, Microscopy, Fluorescence, Models, Biological, Models, Genetic, Multienzyme Complexes, NF-kappa B, Neurons, Nuclear Proteins, Precipitin Tests, Proteasome Endopeptidase Complex, Protein Binding, Proto-Oncogene Proteins c-jun, RNA, Receptors, Cytoplasmic and Nuclear, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Stem Cells, Transcription Factors, Transcriptional Activation, Transducin, Ubiquitin
Cell
Date: Feb. 20, 2004
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