Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adipocytes / cytology
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Animals
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Cell Differentiation
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Cell Nucleus / metabolism*
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Cells, Cultured
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Cysteine Endopeptidases / metabolism
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Embryo, Mammalian / cytology
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Endothelium, Vascular / cytology
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Gene Deletion
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Genetic Vectors
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Ligands
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Mice
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Microscopy, Fluorescence
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Models, Biological
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Models, Genetic
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Multienzyme Complexes / metabolism
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NF-kappa B / metabolism
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Neurons / cytology
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Nuclear Proteins / metabolism
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Precipitin Tests
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Proteasome Endopeptidase Complex
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Protein Binding
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Proto-Oncogene Proteins c-jun / metabolism
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RNA / chemistry
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Receptors, Cytoplasmic and Nuclear / metabolism
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Stem Cells / metabolism
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Transcription Factors / metabolism
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Transcriptional Activation*
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Transducin / metabolism
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Ubiquitin / metabolism
Substances
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Ligands
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Multienzyme Complexes
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NF-kappa B
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Nuclear Proteins
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Proto-Oncogene Proteins c-jun
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Receptors, Cytoplasmic and Nuclear
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Repressor Proteins
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TBL1XR1 protein, human
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Tbl1x protein, mouse
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Transcription Factors
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Ubiquitin
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RNA
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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Transducin