DACH1 inhibits transforming growth factor-beta signaling through binding Smad4.
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-beta (TGF-beta)-induced apoptosis. DACH1 repressed TGF-beta induction of AP-1 and Smad signaling in gene reporter assays and repressed endogenous TGF-beta-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-beta-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-beta signaling by interacting with NCoR and Smad4.
Wu
Kongming
K
Lombardi Cancer Center, Department of Oncology, Georgetown University, Washington, D. C. 20057, USA.
Yang
Ying
Y
Wang
Chenguang
C
Davoli
Maria A
MA
D'Amico
Mark
M
Li
Anping
A
Cveklova
Kveta
K
Kozmik
Zbynek
Z
Lisanti
Michael P
MP
Russell
Robert G
RG
Cvekl
Ales
A
Pestell
Richard G
RG
D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D011485:Protein Binding; D015398:Signal Transduction; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
C486747:DACH1 protein, human; D004268:DNA-Binding Proteins; D005136:Eye Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta