Dax-1 and steroid receptor RNA activator (SRA) function as transcriptional coactivators for steroidogenic factor 1 in steroidogenesis

Mol Cell Biol. 2009 Apr;29(7):1719-34. doi: 10.1128/MCB.01010-08. Epub 2009 Feb 2.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenal Cortex / cytology
  • Adrenal Cortex / metabolism
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Cell Line
  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Intracellular Space / metabolism
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutant Proteins / metabolism
  • Nuclear Receptor Coactivator 2 / metabolism
  • Phosphoproteins / genetics
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Transport
  • RNA, Long Noncoding
  • RNA, Small Interfering / metabolism
  • RNA, Untranslated / metabolism*
  • Receptors, Retinoic Acid / metabolism*
  • Repressor Proteins / metabolism*
  • Steroidogenic Factor 1 / chemistry
  • Steroidogenic Factor 1 / metabolism*
  • Steroids / biosynthesis*
  • Testis / metabolism
  • Trans-Activators / metabolism*
  • Transcription, Genetic*
  • Transcriptional Activation / genetics

Substances

  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • Mutant Proteins
  • NCOA2 protein, human
  • NR0B1 protein, human
  • Nr0b1 protein, mouse
  • Nuclear Receptor Coactivator 2
  • Phosphoproteins
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • RNA, Untranslated
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Steroidogenic Factor 1
  • Steroids
  • Trans-Activators
  • steroid receptor RNA activator
  • steroidogenic acute regulatory protein