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Molecular Endocrinology, doi:10.1210/me.2004-0043
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Molecular Endocrinology 18 (8): 1929-1940
Copyright © 2004 by The Endocrine Society

The Atypical Orphan Nuclear Receptor DAX-1 Interacts with Orphan Nuclear Receptor Nur77 and Represses Its Transactivation

Kwang-Hoon Song, Yun-Young Park, Ki Cheol Park, Cheol Yi Hong, Jin Hee Park, Minho Shong, Keesook Lee and Hueng-Sik Choi

Hormone Research Center, School of Biological Sciences and Technology (K.-H.S., Y.-Y.P., C.Y.H., J.H.P., K.L., H.-S.C.), Chonnam National University, Gwangju 500-757, Korea; and Laboratory of Endocrine Cell Biology (K.C.P., M.S.), National Research Laboratory Program, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 301-721, Korea

Address all correspondence and requests for reprints to: Hueng-Sik Choi, Ph.D., Hormone Research Center, Chungnam National University, Gwangju 500-757, Republic of Korea. E-mail: hsc{at}chonnam.ac.kr.

DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on the X chromosome, gene 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 glutathione-S-transferase 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 steroid receptor coactivator-1 for the binding of Nur77. Moreover, DAX-1 repressed Nur77- and LH-dependent increase of cytochrome P450 protein 17 promoter activity in transient transfection assays. Furthermore, Nur77-mediated transactivation was significantly increased by down-regulation of DAX-1 expression with DAX-1 small interfering RNA 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   DAX1  |  NGFIB  |  NURR1  |  NOR1
Coregulators:   SRC-1



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