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J. Biol. Chem., Vol. 279, Issue 19, 19764-19774, May 7, 2004

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Transcriptional Regulation of Mouse µ Opioid Receptor Gene by PU.1^*

Cheol Kyu Hwang, Chun Sung Kim, Hack Sun Choi, Scott R. McKercher¶, and Horace H. Loh

From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455 and ^¶The Burnham Institute, Center for Neuroscience and Aging, La Jolla, California 92037

We previously reported that the 34-bp cis-acting element of the mouse µ opioid receptor (MOR) gene represses transcription of the MOR gene from the distal promoter. Using a yeast one-hybrid screen to identify potential transcription factors of the MOR promoter, we have identified PU.1 as one of the candidate genes. PU.1 is a member of the ets family of transcription factors, expressed predominantly in hematopoietic cells and microglia of brain. PU.1 plays an essential role in the development of both lymphoid and myeloid lineages. Opioids exert neuromodulatory as well as immunomodulatory effects, which are transduced by MOR. Moreover, MOR-deficient mice exhibit increased proliferation of hematopoietic cells, suggesting a possible link between the opioid system and hematopoietic development. The PU.1 protein binds to the 34-bp element of the MOR gene in a sequence-specific manner confirmed by electrophoretic mobility shift assay and supershift assays. We have also determined endogenous PU.1 interactions with the 34-bp element of MOR promoter by chromatin immunoprecipitation assays. In co-transfection studies PU.1 represses MOR promoter reporter constructs through its PU.1 binding site. When the PU.1 gene is disrupted as in PU.1 knock-out mice and using small interfering RNA-based strategy in RAW264.7 cells, the transcription of the endogenous target MOR gene is increased significantly. This increase is probably mediated through modification of the chromatin structure, as suggested by the reversal of the PU.1-mediated repression of MOR promoter activity after trichostatin A treatment in neuroblastoma NMB cells. Our results suggest that PU.1 may be an important regulator of the MOR gene, particularly in brain and immune cells.

Received for publication, January 23, 2004 , and in revised form, March 3, 2004.

^* This work was supported by National Institutes of Health Research Grants DA00564, DA01583, DA11806, and K05-DA70554 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: hwang025{at}umn.edu.

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