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Papers In Press, published online ahead of print May 6, 2004
Internal Medicine, Division of Bone and Mineral Diseases, Washington University Medical Center, St. Louis, MO 63110
Corresponding Author: dtowler{at}im.wustl.edu
Msx2 promotes osteogenic lineage allocation from mesenchymal progenitors, but inhibits terminal differentiation demarcated by osteocalcin (OC) gene expression. Msx2 inhibits OC expression by targeting the Fibroblast Growth Factor responsive element (OCFRE), a 42 bp DNA domain in the OC gene bound by MINT and Runx2/Cbfa1. To better understand Msx2 regulation of the OCFRE, we have studied functional interactions between MINT -- the Msx2 interacting nuclear target protein – and Runx2, a master regulator of osteoblast differentiation. In MC3T3E1 osteoblasts (with endogenous Runx2 and FGFR2), MINT augments transcription driven by the OCFRE that is further enhanced by FGF2 treatment. OCFRE regulation can be reconstituted in the naïve CV1 fibroblast cell background. In CV1 cells, MINT synergizes with Runx2 to enhance OCFRE activity in the presence of activated FGFR2. The RRM domain of MINT (binds the OCFRE) is required. Runx2 structural studies reveal that synergy with MINT uniquely requires Runx2 Activation Domain 3 (AD3). In confocal immunofluorescence microscopy, MINT adopts a reticular nuclear matrix distribution that overlaps transcriptionally active osteoblast chromatin, extensively co-localizing with the phosphorylated RNA polymerase II (RNAP IIo) meshwork. MINT only partially co-localizes with Runx2; however, co-localization is enhanced 2.5-fold by FGF2 stimulation. Msx2 abrogates Runx2-MINT OCFRE activation, and MINT-directed RNA interference reduces endogenous OC expression. In chromatin immunoprecipitation assays, Msx2 selectively inhibits Runx2 binding to OC chromatin. Thus, MINT enhances Runx2 activation of multiprotein complexes assembled by the OCFRE. Msx2 targets this complex as a mechanism of transcriptional inhibition. In osteoblasts, MINT may serve as a nuclear matrix platform that organizes and integrates osteogenic transcriptional responses.
J. Biol. Chem, 10.1074/jbc.M314098200
Submitted on December 23, 2003
Revised on April 15, 2004
Accepted on May 6, 2004
MINT, the Msx2 interacting nuclear matrix target, enhances runx2 - dependent activation of the osteocalcin fibroblast growth factor response element
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