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Molecular and Cellular Biology, April 2009, p. 1719-1734, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01010-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Dax-1 and Steroid Receptor RNA Activator (SRA) Function as Transcriptional Coactivators for Steroidogenic Factor 1 in Steroidogenesis{triangledown}

Bin Xu,1* Wei-Hsiung Yang,1,2 Isabelle Gerin,3 Chang-Deng Hu,4 Gary D. Hammer,1 and Ronald J. Koenig1

Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48109-5678,1 Department of Biomedical Science, Mercer University School of Medicine, Savannah, Georgia 31404,2 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109,3 Department of Medical Chemistry and Molecular Pharmacology, Purdue Cancer Center, Purdue University, West Lafayette, Indiana 479074

Received 26 June 2008/ Returned for modification 6 August 2008/ Accepted 20 January 2009

The nuclear receptor steroidogenic factor 1 (SF-1) is essential for adrenal development and steroidogenesis. The atypical orphan nuclear receptor Dax-1 binds to SF-1 and represses SF-1 target genes. Paradoxically, however, loss-of-function mutations of Dax-1 also cause adrenal hypoplasia, suggesting that Dax-1 may function as an SF-1 coactivator under some circumstances. Indeed, we found that Dax-1 can function as a dosage-dependent SF-1 coactivator. Both SF-1 and Dax-1 bind to steroid receptor RNA activator (SRA), a coactivator that functions as an RNA. The coactivator TIF2 also associates with Dax-1 and synergistically coactivates SF-1 target gene transcription. A naturally occurring Dax-1 mutation inhibits this transactivation, and the mutant Dax-1-TIF2 complex mislocalizes in living cells. Coactivation by Dax-1 is abolished by SRA knockdown. The expression of the steroidogenic gene products steroidogenic acute regulatory protein (StAR) and melanocortin 2 receptor is reduced in adrenal Y1 cells following the knockdown of endogenous SRA. Similarly, the knockdown of endogenous Dax-1 downregulates the expression of the steroidogenic gene products CYP11A1 and StAR in both H295R adrenal and MA-10 Leydig cells. These findings reveal novel functions of SRA and Dax-1 in steroidogenesis and adrenal biology.

* Corresponding author. Mailing address: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, 5562 MSRBII, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5678. Phone: (734) 647-2883. Fax: (734) 936-6684. E-mail: bxu{at}umich.edu

{triangledown} Published ahead of print on 2 February 2009.

Molecular and Cellular Biology, April 2009, p. 1719-1734, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01010-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • LaVoie, H. A., King, S. R. (2009). Transcriptional Regulation of Steroidogenic Genes: STARD1, CYP11A1 and HSD3B. Exp. Biol. Med. 234: 880-907 [Abstract] [Full Text]  
  • Kim, A. C., Barlaskar, F. M., Heaton, J. H., Else, T., Kelly, V. R., Krill, K. T., Scheys, J. O., Simon, D. P., Trovato, A., Yang, W.-H., Hammer, G. D. (2009). In Search of Adrenocortical Stem and Progenitor Cells. Endocr. Rev. 30: 241-263 [Abstract] [Full Text]  


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