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

Cell. 2004 Feb 20;116(4):511-26. doi: 10.1016/s0092-8674(04)00133-3.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • NF-kappa B / metabolism
  • Neurons / cytology
  • Nuclear Proteins / metabolism
  • Precipitin Tests
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA / chemistry
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Stem Cells / metabolism
  • Transcription Factors / metabolism
  • Transcriptional Activation*
  • Transducin / metabolism
  • Ubiquitin / metabolism

Substances

  • Ligands
  • Multienzyme Complexes
  • NF-kappa B
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-jun
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • TBL1XR1 protein, human
  • Tbl1x protein, mouse
  • Transcription Factors
  • Ubiquitin
  • RNA
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Transducin