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Submitted on February 2, 2004
Accepted on May 11, 2004
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757 Korea, Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 301-721 Korea
* To whom correspondence should be addressed. E-mail: hsc{at}chonnam.ac.kr.
DAX-1 (NROB1) is an atypical member of the nuclear receptor family, which lacks the classical zinc-finger DNA-binding domain and acts as a coregulator of a number of nuclear receptors. In this study, we have found that DAX-1 is a novel coregulator of the orphan nuclear receptor Nur77 (NR4A1). We demonstrate that DAX-1 represses the Nur77 transactivation by transient transfection assays. Specific interaction between Nur77 and DAX-1 was detected by coimmunoprecipitation, yeast two-hybrid, and GST-pull down assays. The ligand binding domain of DAX-1 and the activation function-2 domain of Nur77 were determined as the direct interaction domains between DAX-1 and Nur77. In vitro competition binding assay showed that DAX-1 repressed Nur77 transactivation through the competition with SRC-1 coactivator for the binding of Nur77. Moreover, DAX-1 repressed Nur77- and LH-dependent increase of CYP17 promoter activity in transient transfection assays. Furthermore, Nur77-mediated transactivation was significantly increased by down-regulation of DAX-1 expression with DAX-1 siRNA in testicular Leydig cell line, K28. LH treatment induced a transient increase in Nur77 mRNA, whereas LH repressed DAX-1 expression in a time- and dose-dependent manner in K28 cells. In addition, immunohistochemical analysis showed the expression of Nur77 in mouse testicular Leydig cells. These results suggest that DAX-1 acts as a novel coregulator of the orphan nuclear receptor Nur77, and that the DAX-1 may play a key role in the regulation of Nur77-mediated steroidogenesis in testicular Leydig cells.
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