Control and counter-control of TGF-beta activity through FAST and Runx (CBFa) transcriptional elements in osteoblasts.
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-beta 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-beta 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-beta receptor I gene expression in osteoblasts and thereby reduces TGF-beta 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-beta-dependent events in restricted ways.
Ji
C
C
Department of Surgery, Plastic Surgery Section, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Eickelberg
O
O
McCarthy
T L
TL
Centrella
M
M
D030201:Activin Receptors, Type I; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology; D009363:Neoplasm Proteins; D010006:Osteoblasts / Q000378:metabolism* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000502:physiology
D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat