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J. Biol. Chem., Vol. 278, Issue 14, 11937-11944, April 4, 2003
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From the University of Minnesota Cancer Center, Department of
Orthopaedic Surgery and Graduate Program in Microbiology, Immunology
and Cancer Biology, Minneapolis, Minnesota 55455
Functional control of the transcription factor
Runx2 is crucial for normal bone formation. Runx2 is detectable
throughout osteoblast development and maturation and temporally
regulates several bone-specific genes. In this study, we identified a
novel post-translational mechanism regulating
Runx2-dependent activation of the osteocalcin promoter. A
functional binding site for the high mobility group protein lymphoid
enhancer-binding factor 1 (LEF1) was found adjacent to the proximal
Runx2-binding site in the osteocalcin promoter. In transcription
assays, LEF1 repressed Runx2-induced activation of the mouse
osteocalcin 2 promoter in several osteoblast lineage cell lines.
Mutations in the LEF1-binding site increased the basal activity of the
osteocalcin promoter; however, the LEF1 recognition site in the
osteocalcin promoter was surprisingly not required for LEF1 repression.
A novel interaction between the DNA-binding domains of Runx2 and LEF1
was identified and found crucial for LEF1-mediated repression of Runx2.
LEF1 is a nuclear effector of the Wnt/LRP5/
Lymphoid Enhancer Factor-1 and
-Catenin Inhibit
Runx2-dependent Transcriptional Activation of the
Osteocalcin Promoter*
-catenin signaling
pathway, which is also essential for osteoblast proliferation and
normal skeletal development. A constitutively active -catenin
enhanced LEF1-dependent repression of Runx2. These data
identify a novel mechanism of regulating Runx2 activity in osteoblasts
and link Runx2 transcriptional activity to -catenin signaling.
*
This work was supported by American Cancer Society Grant
IRG-58-001-43-17, by the University of Minnesota Cancer Center, and by
the Office of the Vice President for Research and Dean of the Graduate
School at the University of Minnesota.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: Univ. of Minnesota
Cancer Center, MMC 806, 420 Delaware St. SE, Minneapolis, MN 55455. Tel.: 612-626-3365; Fax: 612-626-4915; E-mail:
weste047@umn.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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