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J. Biol. Chem., Vol. 280, Issue 6, 4785-4791, February 11, 2005

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Menin Suppresses Osteoblast Differentiation by Antagonizing the AP-1 Factor, JunD^*

Junko Naito, Hiroshi Kaji, Hideaki Sowa, Geoffrey N. Hendy¶, Toshitsugu Sugimoto||, and Kazuo Chihara

From the Division of Endocrinology/Metabolism, Neurology and Hematology/Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan and the ^¶Departments of Medicine, Physiology and Human Genetics, McGill University, Montreal, Quebec H3A 1A1, Canada

Mice null for menin, the product of the multiple endocrine neoplasia type 1 (MEN1) gene, exhibit cranial and facial hypoplasia suggesting a role for menin in bone formation. We have shown previously that menin is required for the commitment of multipotential mesenchymal stem cells into the osteoblast lineage in part by interacting with the bone morphogenetic protein (BMP)-2 signaling molecules Smad1/5, and the key osteoblast transcriptional regulator, Runx2 (Sowa H., Kaji, H., Hendy, G. N., Canaff, L., Komori, T., Sugimoto, T., and Chihara, K. (2004) J. Biol. Chem. 279, 40267–40275). However, menin inhibits the later differentiation of committed osteoblasts. The activator protein-1 (AP-1) transcription factor, JunD, is expressed in osteoblasts and has been shown to interact with menin in other cell types. Here, we examined the consequences of menin-JunD interaction on osteoblast differentiation in mouse osteoblastic MC3T3-E1 cells. JunD expression, assessed by immunoblot, gradually increased during osteoblast differentiation. Stable expression of JunD enhanced expression of the differentiation markers, Runx2, type 1 collagen (COL1), and osteocalcin (OCN) and alkaline phosphatase (ALP) activity and mineralization. Hence, JunD promotes osteoblast differentiation. In MC3T3-E1 cells in which menin expression was reduced by stable menin antisense DNA transfection, JunD levels were increased. When JunD and menin were co-transfected in MC3T3-E1 cells, they co-immunoprecipitated. JunD overexpression increased the transcriptional activity of an AP-1 luciferase reporter construct, and this activity was reduced by co-transfection of menin. Therefore, JunD and menin interact both physically and functionally in osteoblasts. Furthermore, menin overexpression inhibited the ALP activity induced by JunD. In conclusion, the data suggest that menin suppresses osteoblast maturation, in part, by inhibiting the differentiation actions of JunD.

Received for publication, July 19, 2004 , and in revised form, November 22, 2004.

^* This work was supported in part by a grant from Kanzawa Medical Research Foundation (to H. K.), a grant-in-aid from the Ministry of Science, Education, and Culture of Japan, No. 15590977 (to H. K.), a grant-in-aid from the Hormone Receptor Abnormality Research Committee Ministry of Health and Welfare of Japan (to T. S.), and Canadian Institutes of Health Research Grant MOP-9315 (to G. N. H.). 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.

^|| Present address: Division of Endocrinology/Metabolism and Hematology/Oncology, Shimane University School of Medicine, 89-1, Enyacho, Izumo, Shimane 693-8501, Japan.

To whom correspondence should be addressed. Tel.: 81-78-382-5885; Fax: 81-78-382-5899; E-mail: hiroshik{at}med.kobe-u.ac.jp.

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