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J. Biol. Chem., Vol. 277, Issue 2, 1316-1323, January 11, 2002
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From the CCAAT/enhancer-binding proteins
(C/EBP) are critical determinants for cellular differentiation and cell
type-specific gene expression. Their functional roles in osteoblast
development have not been determined. We addressed a key component of
the mechanisms by which C/EBP factors regulate transcription of a
tissue-specific gene during osteoblast differentiation. Expression of
both C/EBP
CCAAT/Enhancer-binding Proteins (C/EBP)
and 
Activate Osteocalcin Gene Transcription and Synergize with Runx2 at the
C/EBP Element to Regulate Bone-specific Expression*
§,§,,,,, and
Department of Cell Biology, University of
Massachusetts Medical School, Worcester, Massachusetts 01655-0106 and
the ¶ Departmento de Biologia Molecular, Universidad de
Concepcion, Casilla 160-C Concepcion, Chile
and C/EBP
increases from the growth to maturation
developmental stages and, like the bone-specific osteocalcin (OC) gene,
is also stimulated 3-6-fold by vitamin D3, a
regulator of osteoblast differentiation. We characterized a C/EBP
enhancer element in the proximal promoter of the rat osteocalcin gene,
which resides in close proximity to a Runx2 (Cbfa1) element, essential
for tissue-specific activation. We find that C/EBP and Runx2 factors
interact together in a synergistic manner to enhance OC transcription
(35-40-fold) in cell culture systems. We show by mutational analysis
that this synergism is mediated through the C/EBP-responsive element in
the OC promoter and by a direct interaction between Runx2 and C/EBP.
Furthermore, we have mapped a domain in Runx2 necessary for this
interaction by immunoprecipitation. A Runx2 mutant lacking this
interaction domain does not exhibit functional synergism. We conclude
that, in addition to Runx2 DNA binding functions, Runx2 can also form a
protein complex at C/EBP sites to regulate transcription. Taken together, our findings indicate that C/EBP is a principal
transactivator of the OC gene and the synergism with Runx2 suggests
that a combinatorial interaction of these factors is a principal
mechanism for regulating tissue-specific expression during osteoblast differentiation.
*
This work was supported by National Institutes of Health
Grants DE12528, AR39588, and AR45689.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Cell
Biology, University of Massachusetts Medical School, 55 Lake Ave. N.,
Worcester, MA 01655-0106. Tel.: 508-856-5625; Fax: 508-856-6800; E-mail: jane.lian@umassmed.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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