Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST).
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.
Sevetson
Brad
B
Functional Genomics Department, Amgen Corp, Seattle, Washington 98101, USA.
Taylor
Scott
S
Pan
Yang
Y
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D050659:Core Binding Factor Alpha 1 Subunit; D025461:Feedback, Physiological; D017353:Gene Deletion; D015870:Gene Expression / Q000502:physiology; D005819:Genetic Markers / Q000235:genetics*; D006023:Glycoproteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D017570:MyoD Protein / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D012516:Osteosarcoma; D011401:Promoter Regions, Genetic / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D017570:MyoD Protein; D009363:Neoplasm Proteins; C422903:SOST protein, human; C486030:Sost protein, mouse; D014157:Transcription Factors