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

Valentina Perissi, Aneel Aggarwal, Christopher K. Glass, David W. Rose, Michael G. Rosenfeld

Research output: Contribution to journalArticlepeer-review

468 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)511-526
Number of pages16
JournalCell
Volume116
Issue number4
DOIs
StatePublished - 20 Feb 2004

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