SIP1 (Smad interacting protein 1) and delta EF1 (delta-crystallin enhancerbinding factor) are structurally similar transcriptional repressors - A current survey of their functions and mechanisms of action in transforming growth factor-beta signalling

Background: Smad proteins are intracellular mediators of transforming growt h factor-beta (TGF beta) signalling that regulate gene expression by intera cting with different classes of transcription factors including DNA-binding multi-zinc finger proteins. One of these, Smad interacting protein 1 (SIP1 ), is a novel two-handed zinc-finger protein that displays strong similarit y with the transcriptional repressor delta -crystallin enhancer binding fac tor (delta EF1). Here, we summarize what is known about the mechanism of ac tion of both proteins and their role in vertebrate embryogenesis. Our data are discussed together with the present knowledge on other zinc-finger cont aining Smad interacting proteins. Methods: The activities and function of SIP1 have been analysed through doc umentation of expression patterns, the effect of over-expression of SIP1 on target-gene expression, and promoter studies using Xenopus embryos. Moreov er, S1P1/Smad complexes and their association with target promoter DNA were analyzed in biochemical studies. Results: SIP1 is a transcriptional repressor displaying overlapping DNA bin ding specificities with delta EF1. An in vivo target of SIP1 in Xenopus is a gene required for the formation of mesoderm, Brachyury (XBra). Our data i ndicate that SIP1 is required to confine XBra gene expression to the mesode rm. Furthermore, the expression pattern in Xenopus invites us to speculate that SIP1 plays a role in specification/differentiation of neuroectoderm. U nlike delta EF1, SIP1 can bind directly to activated receptor regulated Sma ds (R-Smads) and recruit them to the DNA. This indicates that Smads may mod ulate the activity of SIP1 as a transcriptional repressor. Conclusions: Our data point to a role of SIP1 in developmental processes re gulated by members of the TGF beta family such as induction of mesoderm (me diated through activin-like signalling) and inhibition of neuroectoderm for mation (mediated by bone morphogenetic proteins [BMPs]). Whereas SIP1 could act in TGF beta signal transduction by virtue of interaction with activate d R-Smads, genetic studies in the mouse indicate that delta EF1 may act in certain TGF beta :pathways-i.e., BMPs and growth and differentiation factor s (GDFs)-as well. The molecular mechanisms by which these transcriptional r epressors act, as well as the function of the SIP1/Smad interaction, remain to be elucidated. Clinical Relevance: Mutations in components of the TGF beta signalling path ways have been associated with disease and congenital malformations. We ant icipate that identification of Smad interacting transcription factors inclu ding SIP1 and their targets will help us to understand the molecular basis of certain pathologies.