SIP1 (Smad interacting protein 1) and deltaEF1 (delta-crystallin enhancer binding factor) are structurally similar transcriptional repressors.
BACKGROUND
Smad proteins are intracellular mediators of transforming growth factor-beta (TGFbeta) signalling that regulate gene expression by interacting 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 similarity with the transcriptional repressor delta-crystallin enhancer binding factor (deltaEF1). Here, we summarize what is known about the mechanism of action of both proteins and their role in vertebrate embryogenesis. Our data are discussed together with the present knowledge on other zinc-finger containing Smad interacting proteins.


METHODS
The activities and function of SIP1 have been analysed through documentation of expression patterns, the effect of over-expression of SIP1 on target-gene expression, and promoter studies using Xenopus embryos. Moreover, S1P1/Smad complexes and their association with target promoter DNA were analyzed in biochemical studies.


RESULTS
SIP1 is a transcriptional repressor displaying overlapping DNA binding specificities with deltaEF1. An in vivo target of SIP1 in Xenopus is a gene required for the formation of mesoderm, Brachyury (XBra). Our data indicate that SIP1 is required to confine XBra gene expression to the mesoderm. Furthermore, the expression pattern in Xenopus invites us to speculate that SIP1 plays a role in specification/differentiation of neuroectoderm. Unlike deltaEF1, SIP1 can bind directly to activated receptor regulated Smads (R-Smads) and recruit them to the DNA. This indicates that Smads may modulate the activity of SIP1 as a transcriptional repressor.


CONCLUSIONS
Our data point to a role of SIP1 in developmental processes regulated by members of the TGFbeta family such as induction of mesoderm (mediated through activin-like signalling) and inhibition of neuroectoderm formation (mediated by bone morphogenetic proteins [BMPs]). Whereas SIP1 could act in TGFbeta signal transduction by virtue of interaction with activated R-Smads, genetic studies in the mouse indicate that deltaEF1 may act in certain TGFbeta pathways-i.e., BMPs and growth and differentiation factors (GDFs)-as well. The molecular mechanisms by which these transcriptional repressors act, as well as the function of the SIP1/Smad interaction, remain to be elucidated.


CONCLUSIONS
Mutations in components of the TGFbeta signalling pathways have been associated with disease and congenital malformations. We anticipate that identification of Smad interacting transcription factors including SIP1 and their targets will help us to understand the molecular basis of certain pathologies.
University of Leuven, Belgium.
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LA
van Grunsven
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A
Schellens
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D
Huylebroeck
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Verschueren
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000071799:Zinc Finger E-box-Binding Homeobox 1
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D051785:Smad Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1