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Originally published In Press as doi:10.1074/jbc.M206482200 on July 26, 2002

J. Biol. Chem., Vol. 277, Issue 40, 37280-37291, October 4, 2002
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Regulation of Osteocalcin Gene Expression by a Novel Ku Antigen Transcription Factor Complex*

David M. WillisDagger §, Arleen P. LoewyDagger , Nichole Charlton-KachigianDagger , Jian-Su ShaoDagger , David M. Ornitz§, and Dwight A. TowlerDagger §

From the Departments of Dagger  Medicine and § Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

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 -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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF112670.

To whom correspondence should be addressed: Washington University Medical Center, Division of Bone and Mineral Diseases, Barnes-Jewish Hospital, North Campus, 216 South Kingshighway Blvd., St. Louis, MO 63110. Tel.: 314-454-7434; Fax: 314-454-5047; E-mail: dtowler@im.wustl.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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