Smad transcriptional corepressors in TGF beta family signaling

The known Smad transcriptional repressors appear to play multiple roles in modulating TGF beta-activated transcriptional responses. As detailed in Fig. 4, in the [figure: see text] absence of TGF beta signals, Ski/Sno prevent the activation of transcription by Smad proteins that find their way to the nucleus. Following TGF beta stimulation, the interaction with Ski/Sno is lost and these proteins are degraded. The free, activated Smad complex then enters the nucleus, where it can form two different kinds of transcriptional complexes: one involving interactions with general transcriptional coactivators, resulting in transcriptional activation, and the alternate complex, in which coactivators are displaced by a complex of corepressors recruited via a protein such as TGIF. The relative levels of these two complexes formed appear to be determined by the levels of available Smad coactivators and corepressors present within the cell. Once Smad transcriptional complexes have been formed, they can be further modulated by corepressors in at least two ways. TGF beta itself appears to upregulate SnoN expression, perhaps resulting in negative feedback on the activating Smad complexes. The balance between coactivators and corepressors within the cell can also be altered by other signaling inputs, and it appears that the stabilization of TGIF in response to activation of the MAP kinase pathway is able to shift the balance towards transcriptional repression. The scheme of action of Smad corepressors, represented in Fig. 4, is based on the initial analyses of these factors, and the challenge for the future is to more fully understand the precise physiological roles of Smad corepressors. Determining the roles they play in modulating responses to TGF beta family ligands during development, together with an analysis of the contributions of mutations that affect Smad corepressor function to genetic diseases such as HPE and to cancer will also be of great interest. Additionally, a better understanding of the events within the nucleus following BMP signaling may reveal the presence not only of more BMP-specific Smad recruiters, but also of BMP Smad-specific corepressors.