Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3.

Transforming growth factor-beta (TGF-beta) inhibits osteoblast differentiation through inhibition of the function of Runx2 (Cbfa1) by Smad3. The mechanism through which TGF-beta/Smad3 inhibits Runx2 function has not been characterized. We show that TGF-beta induces histone deacetylation, primarily of histone H4, at the osteocalcin promoter, which is repressed by TGF-beta, and ...
that histone deacetylation is required for repression of Runx2 by TGF-beta. This repression occurs through the action of the class IIa histone deacetylases (HDAC)4 and 5, which are recruited through interaction with Smad3 to the Smad3/Runx2 complex at the Runx2-binding DNA sequence. Accordingly, HDAC4 or 5 is required for efficient TGF-beta-mediated inhibition of Runx2 function and is involved in osteoblast differentiation. Our results indicate that class IIa HDACs act as corepressors for TGF-beta/Smad3-mediated transcriptional repression of Runx2 function in differentiating osteoblasts and are cell-intrinsic regulators of osteoblast differentiation.
Mesh Terms:
Animals, COS Cells, Cercopithecus aethiops, Core Binding Factor Alpha 1 Subunit, DNA-Binding Proteins, Histone Deacetylases, Mesoderm, Mice, NIH 3T3 Cells, Neoplasm Proteins, Osteoblasts, Osteocalcin, Promoter Regions, Genetic, Smad3 Protein, Trans-Activators, Transcription Factors, Transforming Growth Factor beta
EMBO J.
Date: Jul. 20, 2005
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