Mediator is a transducer of Wnt/beta-catenin signaling.
Signal transduction within the canonical Wnt/beta-catenin pathway drives development and carcinogenesis through programmed or unprogrammed changes in gene transcription. Although the upstream events linked to signal-induced activation of beta-catenin in the cytoplasm have been deciphered in considerable detail, much less is known regarding the mechanism by which beta-catenin stimulates target gene transcription in the nucleus. Here, we show that beta-catenin physically and functionally targets the MED12 subunit in Mediator to activate transcription. The beta-catenin transactivation domain bound directly to isolated MED12 and intact Mediator both in vitro and in vivo, and Mediator was recruited to Wnt-responsive genes in a beta-catenin-dependent manner. Disruption of the beta-catenin/MED12 interaction through dominant-negative interference- or RNA interference-mediated MED12 suppression inhibited beta-catenin transactivation in response to Wnt signaling. This study thus identifies the MED12 interface within Mediator as a new component and a potential therapeutic target in the Wnt/beta-catenin pathway.
Department of Molecular Medicine and the Institute of Biotechnology, University of Texas Health Science Center, San Antonio, Texas 78245-3207, USA.
Seokjoong
S
Kim
Xuan
X
Xu
Andreas
A
Hecht
Thomas G
TG
Boyer
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D005799:Genes, Dominant; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D056892:Mediator Complex; D034622:RNA Interference; D011988:Receptors, Thyroid Hormone / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus; D051176:beta Catenin / Q000378:metabolism*
C460107:MED12 protein, human; D056892:Mediator Complex; D011988:Receptors, Thyroid Hormone; D051153:Wnt Proteins; D051176:beta Catenin; D005982:Glutathione Transferase