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.
Howard Hughes Medical Institute, Department of Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla 92093, USA.
Valentina
V
Perissi
Aneel
A
Aggarwal
Christopher K
CK
Glass
David W
DW
Rose
Michael G
MG
Rosenfeld
D017667:Adipocytes / Q000166:cytology; D000818:Animals; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology; D017353:Gene Deletion; D005822:Genetic Vectors; D008024:Ligands; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008957:Models, Genetic; D009097:Multienzyme Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D009687:Nuclear Proteins / Q000378:metabolism; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012313:RNA / Q000737:chemistry; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D015293:Transducin / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D008024:Ligands; D009097:Multienzyme Complexes; D016328:NF-kappa B; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C473691:TBL1XR1 protein, human; C485613:Tbl1x protein, mouse; D014157:Transcription Factors; D025801:Ubiquitin; D012313:RNA; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D015293:Transducin