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Originally published In Press as doi:10.1074/jbc.M104112200 on July 27, 2001
J. Biol. Chem., Vol. 276, Issue 43, 40001-40007, October 26, 2001
Smad-interacting Protein 1 Is a Repressor of
Liver/Bone/Kidney Alkaline Phosphatase Transcription in Bone
Morphogenetic Protein-induced Osteogenic Differentiation of C2C12
Cells*
Przemko
Tylzanowski §,
Kristin
Verschueren¶,
Danny
Huylebroeck¶, and
Frank P.
Luyten
From the Laboratory of Skeletal Development and Joint
Disorders, University of Leuven, Herestraat 49, 3000 Leuven, Belgium
and the ¶ Department of Cell Growth, Differentiation and
Development (VIB-07), the Flanders Interuniversity Institute for
Biotechnology (VIB) and the Laboratory of Molecular Biology, University
of Leuven, Herestraat 49, B-3000 Leuven, Belgium
Up-regulation of liver/bone/kidney alkaline
phosphatase (LBK-ALP) has been associated with the onset of
osteogenesis in vitro. Its transcription can be
up-regulated by bone morphogenetic proteins (BMPs), constitutively
active forms of their cognate receptors, or appropriate Smads.
The promoter of LBK-ALP has been characterized partially,
but not much is known about its transcriptional modulation by BMPs. A
few Smad-interacting transcriptional factors have been isolated to
date. One of them, Smad-interacting protein 1 (SIP1), belongs to the
family of two-handed zinc finger proteins binding to E2-box sequences
present, among others, in the promoter of mouse LBK-ALP. In
the present study we investigated whether SIP1 could be a candidate
regulator of LBK-ALP transcription in C2C12 cells. We
demonstrate that SIP1 can repress LBK-ALP promoter activity induced by constitutively active Alk2-Smad1/Smad5 and that this repression depends on the binding of SIP1 to the CACCT/CACCTG cluster
present in this promoter. Interestingly, SIP1 and alkaline phosphatase expression domains in developing mouse limb are mutually exclusive, suggesting the possibility that SIP1 could also be involved
in the transcriptional regulation of LBK-ALP
in vivo. Taken together, these results offer an intriguing
possibility that ALP up-regulation at the onset of BMP-induced
osteogenesis could involve Smad/SIP1 interactions, resulting in the
derepression of that gene.
*
This work was supported by Flemish Funds for Scientific
Research Grant FWO G.0192.99.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
§
To whom correspondence should be addressed. E-mail:
przemko@med.kuleuven.ac.be.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.
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