The Journal of Bone and Joint Surgery (American) 83:S40-S47 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.
SIP1 (Smad Interacting Protein 1) and  EF1 (-Crystallin Enhancer Binding Factor) are Structurally Similar Transcriptional Repressors
A Current Survey of Their Functions and Mechanisms of Action in Transforming Growth Factor-ß Signalling
L. A. van Grunsven, PhD,
A. Schellens,
D. Huylebroeck, PhD and
K. Verschueren, PhD
From the University of Leuven, Leuven, Belgium
L.A. van Grunsven, PhD
A. Schellens
D. Huylebroeck, PhD
K. Verschueren, PhD
Laboratory of Molecular Biology, KULeuven, Herestraat 49, Leuven,
Belgium. E-mail address for K. Verschueren: kristin{at}med.kuleuven.ac.be
In support of their research or preparation of this manuscript,
one or more of the authors received grants or outside funding from
European Union (CT 98-0216) Fund for Scientific Research - Flanders
(G.0296.98 and G.0243.01) and University of Leuven (OT/00/41). None
of the authors received payments or other benefits or a commitment
or agreement to provide such benefits from a commercial entity.
A commercial entity (a collaboration agreement for collaborative
research between Innogenetics, Inc., and the Flanders Institute
for Biotechnology [VIB] from January 1998 until December 31, 2000)
paid or directed, or agreed to pay or direct, benefits to a research
fund, foundation, educational institution, or other charitable or
nonprofit organization with which the authors are affiliated or
associated.
Background:
Smad proteins are intracellular mediators of transforming growth
factor-ß (TGFß) 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  -crystallin enhancer
binding factor (EF1). 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 EF1. An
in vivo
target of SIP1 in
Xenopus
is a gene required for the formation of mesoderm, Brachyury (
X
Bra). Our data indicate that SIP1 is required to confine
X
Bra 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 EF1, 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 TGFß 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 TGFß signal transduction by virtue of interaction with activated
R-Smads, genetic studies in the mouse indicate that EF1 may act
in certain TGFß 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.
Clinical Relevance:
Mutations in components of the TGFß 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.
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