TBL1-TBLR1 and beta-catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis.
Aberrant Wnt signalling promotes oncogenesis by increasing the nuclear accumulation of beta-catenin to activate downstream target genes. However, the mechanism of beta-catenin recruitment to the Wnt target-gene promoter, a critical step for removing the co-repressor complex, is largely unknown. Here, we report that transducin beta-like protein 1 (TBL1) and its highly related family member TBLR1 were required for Wnt-beta-catenin-mediated transcription. Wnt signalling induced the interaction between beta-catenin and TBL1-TBLR1, as well as their binding to Wnt target genes. Importantly, the recruitment of TBL1-TBLR1 and beta-catenin to Wnt target-gene promoters was mutually dependent on each other. Furthermore, the depletion of TBL1-TBLR1 significantly inhibited Wnt-beta-catenin-induced gene expression and oncogenic growth in vitro and in vivo. Our results unravel two new components required for nuclear beta-catenin function, and have important implications in developing new strategies for inhibiting Wnt-beta-catenin-mediated tumorigenesis.
Li
Jiong
J
Laboratory of Molecular Signalling, Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
Wang
Cun-Yu
CY
D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000502:physiology*; D015293:Transducin / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D051176:beta Catenin / Q000502:physiology*
D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C119542:TBL1X protein, human; C473691:TBL1XR1 protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex; D015293:Transducin