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J. Biol. Chem., Vol. 279, Issue 14, 13849-13858, April 2, 2004

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Cbfa1/RUNX2 Directs Specific Expression of the Sclerosteosis Gene (SOST)^*

Brad Sevetson, Scott Taylor, and Yang Pan¶

From the Functional Genomics Department and Bioinformatics Department, Amgen Corp., Seattle, Washington 98101

Loss-of-function mutations in the sclerosteosis gene (SOST) cause a rare sclerosing bone dysplasia characterized by skeletal overgrowth. Cbfa1/RUNX2 is a key transcriptional regulator of osteoblast function. Here we link these two pathways by demonstrating, via gel shift and transient transfection analyses, that Cbfa1 binding to the proximal SOST promoter contributes to differential SOST expression in two osteosarcoma cell lines. Additionally, an E-box binding motif in the 1.8-kb proximal SOST promoter appears to be functional in SAOS-2 cells, but does not account for SAOS-specific expression of SOST. The regulation of SOST expression by Cbfa1 suggests a potential role for the sclerosteosis gene in homeostatic regulation of osteoblast differentiation and function. Furthermore, the juxtaposition of Cbfa1, E-box, and C/EBP binding sites in the SOST proximal promoter bears an intriguing resemblance to the promoter for osteocalcin, another osteoblast-specific gene with a loss-of-function phenotype of bone overgrowth.

Received for publication, June 13, 2003 , and in revised form, December 23, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This 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. Tel.: 206-265-8614; Fax: 206-217-0349; E-mail: pany{at}amgen.com.

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