DACH1 Inhibits Transforming Growth Factor-β Signaling through Binding Smad4

Kongming Wu, Ying Yang, Chenguang Wang, Maria A. Davoli, Mark D'Amico, Anping Li, Kveta Cveklova, Zbynek Kozmik, Michael P. Lisanti, Robert G. Russell, Ales Cvekl, Richard G. Pestell

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

The vertebrate homologues of Drosophila dachsund, DACH1 and DACH2, have been implicated as important regulatory genes in development. DACH1 plays a role in retinal and pituitary precursor cell proliferation and DACH2 plays a specific role in myogenesis. DACH proteins contain a domain (DS domain) that is conserved with the proto-oncogenes Ski and Sno. Since the Ski/Sno proto-oncogenes repress AP-1 and SMAD signaling, we hypothesized that DACH1 might play a similar cellular function. Herein, DACH1 was found to be expressed in breast cancer cell lines and to inhibit transforming growth factor-β (TGF-β-induced apoptosis. DACH1 repressed TGF-β induction of AP-1 and Smad signaling in gene reporter assays and repressed endogenous TGF-β-responsive genes by microarray analyses. DACH1 bound to endogenous NCoR and Smad4 in cultured cells and DACH1 co-localized with NCoR in nuclear dotlike structures. NCoR enhanced DACH1 repression, and the repression of TGF-β-induced AP-1 or Smad signaling by DACH1 required the DACH1 DS domain. The DS domain of DACH was sufficient for NCoR binding at a Smad4-binding site. Smad4 was required for DACH1 repression of Smad signaling. In Smad4 null HTB-134 cells, DACH1 inhibited the activation of SBE-4 reporter activity induced by Smad2 or Smad3 only in the presence of Smad4. DACH1 participates in the negative regulation of TGF-β signaling by interacting with NCoR and Smad4.

Original languageEnglish (US)
Pages (from-to)51673-51684
Number of pages12
JournalJournal of Biological Chemistry
Volume278
Issue number51
DOIs
StatePublished - Dec 19 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Wu, K., Yang, Y., Wang, C., Davoli, M. A., D'Amico, M., Li, A., Cveklova, K., Kozmik, Z., Lisanti, M. P., Russell, R. G., Cvekl, A., & Pestell, R. G. (2003). DACH1 Inhibits Transforming Growth Factor-β Signaling through Binding Smad4. Journal of Biological Chemistry, 278(51), 51673-51684. https://doi.org/10.1074/jbc.M310021200