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Control and Counter-Control of TGF-ß Activity through FAST and Runx (CBFa) Transcriptional Elements in Osteoblasts

Departments of Surgery (Plastic Surgery Section) (C.J., T.L.M., M.C.) and Pathology (O.E.), Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Michael Centrella, Ph.D., Department of Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8041. E-mail: michael.centrella{at}yale.edu

FAST and Runx (CBFa) transcription factors, which are expressed during specific phases of embryogenesis and tissue patterning, bind directly to Smad proteins and integrate effects induced by various TGF-ß gene family members. The DNA binding sequences for FAST and Runx differ only minimally. The isoform Runx2 (previously termed CBFa1) is highly expressed by osteoblasts and regulates expression of the TGF-ß receptor I in these cells. Here we show that FAST-dependent transcription is endogenously restricted in osteoblasts but can be significantly enhanced by disruption of Runx2 expression. Native and synthetic Runx2 bind to both Runx and FAST binding sequences, whereas FAST-1 efficiently binds only to the FAST binding sequence. However, overexpression of FAST-1 potently suppresses TGF-ß receptor I gene expression in osteoblasts and thereby reduces TGF-ß activity independently of competing for Runx2 at the level of DNA binding. These results provide a new example of how nuclear factors associated with specific developmental states or tissue lineages may influence TGF-ß-dependent events in restricted ways.

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