title: DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis.
abstract: Mutations in the DAX-1 gene are responsible for congenital X-linked adrenal hypoplasia, a disease that is associated with hypogonadotropic hypogonadism. DAX-1 expression is tissue-specific and is finely regulated throughout development, suggesting that it has a role in both adrenal and gonadal function. DAX-1 is an unusual member of the nuclear-receptor superfamily of transcription factors which contains no canonical zinc-finger or any other known DNA-binding motif. Binding sites for DAX-1 are found in the promoters of the dax-1 and StAR (for steroidogenic acute regulatory protein) genes. Here we show that DAX-1 binds DNA and acts as a powerful transcriptional repressor of StAR gene expression, leading to a drastic decrease in steroid production. We provide in vitro and in vivo evidence that DAX-1 binds to DNA hairpin structures. Our results establish DAX-1 as the first member of the nuclear receptor superfamily with novel DNA-binding features and reveal that it has regulatory properties critical to the understanding of its physiological functions.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS-INSERM-ULP BP 163, Strasbourg, France.
authors.forename: E
authors.initials: E
authors.lastname: Zazopoulos
authors.forename: E
authors.initials: E
authors.lastname: Lalli
authors.forename: D M
authors.initials: DM
authors.lastname: Stocco
authors.forename: P
authors.initials: P
authors.lastname: Sassone-Corsi
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D057137:DAX-1 Orphan Nuclear Receptor; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D010750:Phosphoproteins; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D012097:Repressor Proteins; D013256:Steroids; D014157:Transcription Factors; D000098682:Steroidogenic Acute Regulatory Protein; D004247:DNA