Lymphoid enhancer factor-1 and beta-catenin inhibit Runx2-dependent transcriptional activation of the osteocalcin promoter

• Published in: The Journal of biological chemistry Vol. 278; no. 14; pp. 11937 - 11944
• Main Authors: Kahler, Rachel A, Westendorf, Jennifer J
• Format: Journal Article
• Language: English
• Published: United States 04.04.2003
• Subjects: 3T3 Cells; Animals; beta Catenin; Binding Sites - genetics; Cell Differentiation - physiology; Cell Division - physiology; Core Binding Factor Alpha 1 Subunit; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; High Mobility Group Proteins - metabolism; Lymphoid Enhancer-Binding Factor 1; Mice; Mice, Inbred C3H; Neoplasm Proteins; Osteoblasts - cytology; Osteoblasts - physiology; Osteocalcin - genetics; Osteosarcoma; Promoter Regions, Genetic - physiology; Protein Structure, Tertiary; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Rats; Stem Cells - cytology; Stem Cells - physiology; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation - physiology; Tumor Cells, Cultured; Wnt Proteins; Zebrafish Proteins
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M211443200

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/beta-catenin signaling pathway, which is also essential for osteoblast proliferation and normal skeletal development. A constitutively active beta-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 beta-catenin signaling.