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J. Biol. Chem., Vol. 280, Issue 42, 35579-35587, October 21, 2005

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Dlx5 Specifically Regulates Runx2 Type II Expression by Binding to Homeodomain-response Elements in the Runx2 Distal Promoter^*

Mi-Hye Lee, Youn-Jeong Kim, Won-Joon Yoon, Jee-In Kim, Byung-Gyu Kim, Yoo-Seok Hwang, John M. Wozney¶, Xin-Zi Chi||, Suk-Chul Bae||, Kang-Young Choi, Je-Yoel Cho, Je-Yong Choi**, and Hyun-Mo Ryoo1

From the Department of Biochemistry, School of Dentistry and Skeletal Diseases Genome Research Center, and the Departments of Anatomy and ^**Biochemistry, School of Medicine, Kyungpook National University, Daegu 700-422, Korea, ^¶Wyeth Pharmaceuticals, Cambridge, Massachusetts 02140, and the ^||Department of Biochemistry, School of Medicine, Chungbuk National University, Cheongju 361-763, Korea

Two major isoforms of the Runx2 gene are expressed by alternative promoter usage: Runx2 type I (Runx2-I) is derived from the proximal promoter (P2), and Runx2 type II (Runx2-II) is produced by the distal promoter (P1). Our previous results indicate that Dlx5 mediates BMP-2-induced Runx2 expression and osteoblast differentiation (Lee, M.-H., Kim, Y-J., Kim, H-J., Park, H-D., Kang, A-R., Kyung, H.-M., Sung, J-H., Wozney, J. M., Kim, H-J., and Ryoo, H-M. (2003) J. Biol. Chem. 278, 34387-34394). However, little is known of the molecular mechanisms by which Dlx5 up-regulates Runx2 expression in BMP-2 signaling. Here, Runx2-II expression was found to be specifically stimulated by BMP-2 treatment or by Dlx5 overexpression. In addition, BMP-2, Dlx5, and Runx2-II were found to be expressed in osteogenic fronts and parietal bones of the developing cranial vault and Runx2-I and Msx2 in the sutural mesenchyme. Furthermore, Runx2 P1 promoter activity was strongly stimulated by Dlx5 overexpression, whereas Runx2 P2 promoter activity was not. Runx2 P1 promoter deletion analysis indicated that the Dlx5-specific response is due to sequences between -756 and -342 bp of the P1 promoter, where three Dlx5-response elements are located. Dlx5 responsiveness to these elements was confirmed by gel mobility shift assay and site-directed mutagenesis. Moreover, Msx2 specifically suppressed the Runx2 P1 promoter, and the responsible region overlaps with that recognized by Dlx5. In summary, Dlx5 specifically transactivates the Runx2 P1 promoter, and its action on the P1 promoter is antagonized by Msx2.

Received for publication, February 28, 2005 , and in revised form, July 19, 2005.

^* This work was supported by Grants 01-PJ1-PG1-01CH08-0001 and 01-PJ3-PG6-01GN11-0002 from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cell and Developmental Biology, College of Dentistry and Dental Research Inst., Seoul National University, 28 Yeongeon-dong, Jongno-gu, Seoul 110-749, Korea. Tel.: 82-2-740-8743; E-mail: hmryoo{at}snu.ac.kr.

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