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J. Biol. Chem., Vol. 277, Issue 40, 37280-37291, October 4, 2002
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From the Departments of We previously described an
osteocalcin (OC) fibroblast growth factor (FGF)
response element (FRE) DNA binding activity as a target of Msx2
transcriptional regulation. We now identify Ku70, Ku80, and Tbdn100, a
variant of Tubedown-1, as constituents of the purified OCFRE-binding
complex. Northern and Western blot analyses demonstrate expression of
Ku and Tbdn100 in MC3T3E1 osteoblasts. FGF2 treatment
regulates Ku, but not Tbdn100, protein accumulation. Gel supershift
studies confirm sequence-specific DNA binding of Ku in the OCFRE
complex; chromatin immunoprecipitation assays confirm association of Ku
and Tbdn100 with the endogenous OC promoter. In the
promoter region The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF112670.
Regulation of Osteocalcin Gene Expression by a
Novel Ku Antigen Transcription Factor Complex*
§,,,,§¶
Medicine and
§ Molecular Biology and Pharmacology, Washington
University School of Medicine, St. Louis, Missouri 63110
154 to 113, the OCFRE is juxtaposed to OSE2, an
osteoblast-specific element that binds Runx2 (Osf2, Cbfa1). Expression of the Ku·Tbdn100 complex up-regulates both the
basal and Runx2-dependent transcription driven by this
42-bp OC promoter element, reconstituted in CV-1 cells.
Synergistic transactivation occurs in the presence of activated FGF
receptor 2 signaling. Msx2 suppresses Ku- and
Runx2-dependent transcription; suppression is dependent
upon the Msx2 homeodomain NH2-terminal arm and extension. Pull-down assays confirm physical interactions between Ku and these
co-regulatory transcription factors, consistent with the functional
interactions identified. Finally, cultured Ku70 / calvarial cells
exhibit a profound, selective deficiency in OC expression
as compared with wild-type calvarial cells, confirming the biochemical
data showing a role for Ku in OC transcription. In
toto, these data indicate that a novel Ku antigen complex
assembles on the OC promoter, functioning in concert with
Msx2 and Runx2 to regulate OC gene expression.
*
This work was supported by National Institutes of Health
Grants R01 DK52446 and R01 AR43731 (to D. A. T.) and a
pre-doctoral research fellowship from the National Osteoporosis
Foundation (to D. M. W.).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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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