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The notch-responsive transcription factor Hes-1 attenuates osteocalcin promoter activity in osteoblastic cells

✍ Scribed by Ying Zhang; Jane B. Lian; Janet L. Stein; Andre J. van Wijnen; Gary S. Stein

Publisher
John Wiley and Sons
Year
2009
Tongue
English
Weight
302 KB
Volume
108
Category
Article
ISSN
0730-2312

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✦ Synopsis

Abstract

Notch signaling plays a key role in osteoblast differentiation. A major transcriptional downstream regulator of this pathway is the helix–loop–helix (HLH) transcription factor Hairy/Enhancer of Split 1 (Hes‐1). Here we investigated the function of Hes‐1 in osteoblastic cells. Endogenous Hes‐1 gene expression decreases during progression of bone cell phenotype development in MC3T3‐E1 osteoblasts suggesting that it is a negative regulator of osteoblast differentiation. Forced expression of Hes‐1 inhibits osteocalcin (OC) mRNA levels, and luciferase assays indicate that Hes‐1 directly represses OC promoter activity. In vitro and in vivo protein/DNA interaction assays reveal that recombinant Hes‐1 binds specifically to an E‐box in the proximal promoter of the OC gene. Deletion of the Hes‐1 WRPW domain (MHes‐1) that recruits the co‐repressor Groucho abrogates repression of OC promoter activity by Hes‐1, but also blocks Hes‐1 binding to the promoter. The latter result suggests that exogenous Hes‐1 may be recruited to the OC promoter by both protein/DNA and protein/protein interactions. We conclude that the Notch‐responsive Hes‐1 protein is capable of repressing OC gene transcription in osteoblastic cells through an E‐box in the proximal promoter. Hes‐1 may contribute to osteoblast growth and differentiation by controlling basal bone‐specific transcription directly through interactions with transcriptional regulators that are known to bind to the OC gene promoter. J. Cell. Biochem. 108: 651–659, 2009. © 2009 Wiley‐Liss, Inc.

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