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J. Biol. Chem., Vol. 281, Issue 51, 39159-39168, December 22, 2006

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The Repression of Human Differentiation-related Gene NDRG2 Expression by Myc via Miz-1-dependent Interaction with the NDRG2 Core Promoter^*

From the Institute of Molecular Biology and the State Key Laboratory of Cancer Biology, Fourth Military Medical University, 710032 Xi'an, China

The N-myc downstream-regulated gene 1 (ndrg1) is highly expressed in N-myc knock-out mice through an unknown regulatory mechanism. As one member of the human NDRG gene family, NDRG2 encodes a protein highly homologous to Ndrg1. However, it is uncertain whether the expression of human NDRG2 is regulated by Myc because mouse ndrg2 and -3 are not affected by Myc. In this study, we provide the novel evidence that the expression of human NDRG2 is down-regulated by Myc via transcriptional repression. A high level of NDRG2 was observed as Myc expression was reduced in differentiated cells, whereas a low level of NDRG2 was shown following increased Myc expression upon serum stimulation. The ectopic expression of c-Myc dramatically reduces the cellular Ndrg2 protein and mRNA level. We further identified the core promoter region of NDRG2 that is required for Myc repression on NDRG2 transcription, and we verified the interaction of Myc with the core promoter region both in vitro and in vivo. Moreover, the c-Myc-mediated repression of NDRG2 requires association with Miz-1, and possibly the recruitment of other epigenetic factors, such as histone deacetylases, to the promoter. The regulatory function of Myc on NDRG2 gene expression implicated the role of the Ndrg2 in regulating cell differentiation.

Received for publication, June 19, 2006 , and in revised form, October 2, 2006.

^* This work was supported in part by Chinese National Key Basic Research and Development Program 2002CB513007, Program PCSIRT0459 for Changjiang Scholars and Innovative Research Team in University in China, and National Natural Science Foundation of China Grants 30370315, 30228012, and 30670452. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S8.

¹ The first two authors should be regarded as joint first authors.

² Recipient of a University grant for Ph.D. thesis.

³ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, The Fourth Military Medical University, 17 Changle Western Rd., 710032, Xi'an, China. Tel.: 86-29-84774513; Fax: 29-84774513; E-mail: bioyao{at}fmmu.edu.cn.

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