TBL1-related protein 1 (TBLR1/TBL1XR1) and Transducing β-like protein 1 (TBL1X/TBL1) were originally identified as subunits of the co-repressor silencing mediator for retinoic and thyroid hormone receptor (SMRT) and nuclear receptor co-repressor (NCoR) complexes. These two factors are required for the exchange of co-repressor complexes for co-activators by acting as adaptors to recruit the ubiquitin/proteasome machinery that degrades the co-repressor proteins during ligand mediated activation of transcription. Co-factor exchange driven by TBLR1/TBL1XR1 and TBL1X/TBL1 appears to be the mechanism by which c-Jun and NF-κB mediated transcription is activated and is therefore likely to be the mechanism employed by other signal-dependent transcription factors as well. In addition, both TBLR1/TBL1XR1 and TBL1X/TBL1 have essential roles in regulating the Wnt-signaling pathway by recruiting β-catenin to Wnt target genes to activate transcription. Depletion of TBLR1/TBL1XR1 significantly inhibited Wnt-beta-catenin- induced gene expression and oncogenic growth in vitro and in vivo. Research studies have shown that upregulation of TBLR1/TBL1XR1 is observed in a variety of solid tumors, and is correlated with advanced tumor stage, metastasis and poor prognosis.
