Transcription factors belonging to the Smad family are activated in response to signals from TGF-β family members, which in Xenopus embryos are involved in morphogenesis and pattern formation. Direct binding of DNA by Smads is weak; however, Smads can be recruited to DNA by other transcription factors, and these interactions may play an important role in specifying which genes Smads will regulate in a particular cell. Germain et al. studied expression from the Xenopus goosecoid promoter in response to activin, a member of the TGF-β family, in order to identify the transcription factors that recruit activated Smads to the distal element (DE) in this promoter. The activin response required protein synthesis and led to the production of a protein that bound to the DE, as measured by gel-shift assay. The activin-induced DNA-protein complex was further shifted by the addition of Smad2 to the assay, indicating that a ternary complex could be formed. Two members of the paired-like homeodomain transcription factor family, Mixer and Milk, are candidates for the activin-induced DE-binding protein. Analysis of this transcription factor family led to the identification of a Smad interacting motif (SIM) in these homeodomain proteins, as well as in winged-helix proteins that interact with Smad2. The activity of the winged-helix protein Fast-1 was inhibited by a peptide corresponding to the Mixer SIM, suggesting that Smads may bind to a common motif in various transcription factors. The transcription factors would provide DNA binding specificity to recruit Smads to distinct promoter elements.
Germain, S., Howell, M., Esslemont, G.M., and Hill, C.S. (2000) Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif. Genes Dev. 14: 435-451. [Abstract] [Full Text]