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

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.

CUL4 forms an E3 ligase with COP1 and SPA to promote light-induced degradation of PIF1

“…Opposite roles of the same protein in a biological process have been described in association with other factors 36,37 . This is mostly common in transcription factors that recruit activator or repressor complexes to regulate gene expression 38 . Our data also provide a biochemical explanation for a novel signalling mechanism where a well-established master negative regulator complex acts positively to promote plant morphogenesis in response to light.…”

Interactions between the estrogen receptor, its cofactors and microRNAs in breast cancer

“…The majority of those identified are coactivators, recruited by activated, ligand-bound NRs to enhance gene expression, whereas corepressors, of which approximately 40 have been identified, generally interact with unliganded receptors [7] and oppose the actions of coactivators. The balance between coactivators and corepressors defines the outcome of the cellular responses to NR ligands and the switching of corepressors for coactivators can convert a transcription factor from a repressor to an activator of gene expression [8][9][10].…”

A novel PPARγ2 modulator sLZIP controls the balance between adipogenesis and osteogenesis during mesenchymal stem cell differentiation

“…6,7 Upon ligand binding, PPARg undergoes a conformational change and the corepressor complex is replaced by co-activators, including p300, the p160/steroid receptor co-activator (p160/SRC) family, the PPARg-binding protein, PPARg co-activator-1 (PGC-1), and the CREB-binding protein. 7,8 Many transcription …”

“…4,5 The heterodimer is associated with the nuclear receptor corepressor complex that includes histone deacetylase (HDAC), nuclear receptor corepressor (NCoR), and the silencing mediator for retinoid and thyroid receptors in the absence of the PPARg ligand. 6,7 Upon ligand binding, PPARg undergoes a conformational change and the corepressor complex is replaced by co-activators, including p300, the p160/steroid receptor co-activator (p160/SRC) family, the PPARg-binding protein, PPARg co-activator-1 (PGC-1), and the CREB-binding protein. 7,8 Many transcription factors and ligands are involved in expression and function of PPARg.…”

“…6,7 Upon ligand binding, PPARg undergoes a conformational change and the corepressor complex is replaced by co-activators, including p300, the p160/steroid receptor co-activator (p160/SRC) family, the PPARg-binding protein, PPARg co-activator-1 (PGC-1), and the CREB-binding protein. 7,8 Many transcription factors and ligands are involved in expression and function of PPARg. Transcription factors of the CCAAT/enhancer-binding protein (C/EBP) family stimulate PPARg transcription by binding directly to the promoter of PPARg.…”