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J. Biol. Chem., Vol. 279, Issue 45, 46464-46473, November 5, 2004

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Neuron-restrictive Silencer Factor (NRSF) Functions as a Repressor in Neuronal Cells to Regulate the µ Opioid Receptor Gene^*

Chun Sung Kim, Cheol Kyu Hwang, Hack Sun Choi, Kyu Young Song, Ping-Yee Law, Li-Na Wei, and Horace H. Loh

From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

The µ opioid receptor (MOR) is expressed in the central nervous system and specific cell lines with varying expression levels perhaps playing important roles. One of the neuronal-specific transcription regulators, neuron-restrictive silencer factor (NRSF), has been shown to repress the expression of neuron-specific genes in non-neuronal cells. However, we showed here that the neuron-restrictive silencer element (NRSE) of MOR functions as a critical regulator to repress the MOR gene expression in specific neuronal cells depending on NRSF expression level. Using co-transfection studies, we showed that the NRSE of the MOR promoter is functional in NRSF-positive cells (NS20Y and HeLa) but not in NRSF-negative cells (PC12). NRSF binds to the NRSE of the MOR gene in a sequence-specific manner confirmed by supershift and chromatin immunoprecipitation assays, respectively. The suppression of NRSF activity with either trichostatin A or a dominant-negative NRSF induced MOR promoter activity and transcription of the MOR gene. When the NRSF was disrupted in NS20Y and HeLa cells using small interfering RNA, the transcription of the endogenous target MOR gene increased significantly. This provides direct evidence the role of NRSF in the cells and also indicates that NRSF expression is regulated by post-translational modification in neuronal NMB cells. Our data suggested that NRSF can function as a repressor of MOR transcription in specific cells, via a mechanism dependent on the MOR NRSE.

Received for publication, April 1, 2004 , and in revised form, August 9, 2004.

^* This work was supported by National Institutes of Health Research Grants DA00564, DA01583, DA11806, K05-DA70554, DA11190, and DA13926 and by the A&F Stark Fund of the Minnesota Medical Foundation. 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.

To whom correspondence should be addressed: Dept. of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455. Tel.: 612-626-6539; Fax: 612-625-8408; E-mail: kimxx313{at}umn.edu.

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