title: Dax-1 and steroid receptor RNA activator (SRA) function as transcriptional coactivators for steroidogenic factor 1 in steroidogenesis.
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.
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48109-5678, USA. bxu@umich.edu
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Wei-Hsiung
authors.initials: WH
authors.lastname: Yang
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gerin
authors.forename: Chang-Deng
authors.initials: CD
authors.lastname: Hu
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hammer
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Koenig
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering / Q000378:metabolism; D022661:RNA, Untranslated / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D054339:Steroidogenic Factor 1 / Q000737:chemistry / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*; D013737:Testis / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D050505:Mutant Proteins; C498001:NCOA2 protein, human; C539965:NR0B1 protein, human; C539966:Nr0b1 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D010750:Phosphoproteins; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D013256:Steroids; D015534:Trans-Activators; C405423:steroid receptor RNA activator; D000098682:Steroidogenic Acute Regulatory Protein