Smad7:?-catenin complex regulates myogenic gene transcription.

ABSTRACT: Recent reports indicate that Smad7 promotes skeletal muscle differentiation and growth. We previously documented a non-canonical role of nuclear Smad7 during myogenesis, independent of its role in TGF-? signaling. Here further characterization of the myogenic function of Smad7 revealed ?-catenin as a Smad7 interacting protein. Biochemical analysis identified a Smad7 interaction domain (SID) between aa575 and aa683 of ?-catenin. Reporter gene analysis and chromatin immunoprecipitation demonstrated that Smad7 and ?-catenin are cooperatively recruited to the extensively characterized ckm promoter proximal region to facilitate its muscle restricted transcriptional activation in myogenic cells. Depletion of endogenous Smad7 and ?-catenin in muscle cells reduced ckm promoter activity indicating their role during myogenesis. Deletion of the ?-catenin SID substantially reduced the effect of Smad7 on the ckm promoter and exogenous expression of SID abolished ?-catenin function, indicating that SID functions as a trans dominant-negative regulator of ?-catenin activity. ?-catenin interaction with the Mediator kinase complex through its Med12 subunit led us to identify MED13 as an additional Smad7-binding partner. Collectively, these studies document a novel function of a Smad7-MED12/13-?-catenin complex at the ckm locus, indicating a key role of this complex in the program of myogenic gene expression underlying skeletal muscle development and regeneration.

SUBMITTER: Tripathi S 

PROVIDER: S-EPMC6522533 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature