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Molecular and Cellular Biology, February 2006, p. 1002-1013, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.1002-1013.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Receptor Activator of NF-{kappa}B Ligand Regulates the Proliferation of Mammary Epithelial Cells via Id2

Nam-Shik Kim,1,{dagger} Hyun-Ju Kim,1,{dagger} Bon-Kyoung Koo,1 Min-Chul Kwon,1 Young-Woong Kim,1 Yunje Cho,1 Yoshifumi Yokota,2 Josef M. Penninger,3 and Young-Yun Kong1*

Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang 790-783, Kyungbuk, South Korea,1 Department of Biochemistry, Fukui Medical University, Matsuoka 910-1193, Fukui, Japan,2 IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3-5, A-1030 Vienna, Austria3

Received 12 July 2005/ Returned for modification 23 August 2005/ Accepted 19 October 2005

Receptor activator of NF-{kappa}B ligand (RANKL) is a key regulator for mammary gland development during pregnancy. RANKL-deficient mice display impaired development of lobulo-alveolar mammary structures. Similar mammary gland defects have been reported in mice lacking Id2. Here we report that RANKL induces the proliferation of mammary epithelial cells via Id2. RANKL triggers marked nuclear translocation of Id2 in mammary epithelial cells. In vivo studies further demonstrated the defective nuclear translocation of Id2, but the normal expression of cyclin D1, in the mammary epithelial cells of rankl–/– mice. In vitro studies with nuclear localization sequence-tagged Id2 revealed that the nuclear localization of Id2 itself is critical for the downregulation of p21 promoter activity. Moreover, RANKL stimulation failed to induce cell growth and to downregulate p21 expression in Id2–/– mammary epithelial cells. Our results indicate that the inhibitor of helix-loop-helix protein, Id2, is critical to control the proliferation of mammary epithelial cells in response to RANKL stimulation.

* Corresponding author. Mailing address: Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang 790-783, Kyungbuk, South Korea. Phone: 82-54-279-2287. Fax: 82-54-279-2199. E-mail: ykong{at}postech.ac.kr.

{dagger} N.-S.K. and H.-J.K. contributed equally to this study.

Molecular and Cellular Biology, February 2006, p. 1002-1013, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.1002-1013.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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