Sevetson Brad, Taylor Scott, Pan Yang
Functional Genomics Department, Amgen Corp, Seattle, Washington 98101, USA.
J Biol Chem. 2004 Apr 2;279(14):13849-58. doi: 10.1074/jbc.M306249200. Epub 2004 Jan 22.
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.
硬化性骨病基因（SOST）的功能丧失突变会导致一种罕见的硬化性骨发育异常，其特征为骨骼过度生长。Cbfa1/RUNX2是成骨细胞功能的关键转录调节因子。在此，我们通过凝胶迁移和瞬时转染分析证明，Cbfa1与SOST近端启动子的结合促成了两种骨肉瘤细胞系中SOST的差异表达，从而将这两条途径联系起来。此外，1.8 kb的SOST近端启动子中的一个E盒结合基序在SAOS-2细胞中似乎具有功能，但不能解释SOST在SAOS细胞中的特异性表达。Cbfa1对SOST表达的调节表明，硬化性骨病基因在成骨细胞分化和功能的稳态调节中可能发挥作用。此外，SOST近端启动子中Cbfa1、E盒和C/EBP结合位点的并列与骨钙素的启动子有着有趣的相似之处，骨钙素是另一种具有骨过度生长功能丧失表型的成骨细胞特异性基因。
