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Steroidogenic factor 1 - SF1 (Gene NR5A1) Homo sapiensThe NR5A1 gene (map locus Entrez and HGNC: 9q33; Ensembl: 9q33.3) product, steroidogenic factor 1 (SF-1/Ad4BP), is an orphan nuclear receptor. SF-1 is a 461 amino acids long (51.6 kDa) DNA binding (DBD region 10-85) monomer that is post-translationally modified and activated by acetylation at Lys34, Lys38 and Lys72 and/or phosphorylation at Ser203. The nuclear localization signal (NLS) is located downstream of the DBD (region 89-101). The SF-1 ligand binding domain (LBD) spans the 260 to 347 amino acid region, SF-1 binds lipid head groups of phosphatidylinositol (especially PI(3,4)P2 and PI(3,4,5)P3) at Gly341, Tyr436 and Lys440. The DNA consensus sequences 5’-YCAAGGYC-3’ and 5’RRAGGTCA-3’ are binding sites for SF-1. SF-1 is expressed in the anlages, primordial organ cell clusters, of the adrenogenital primordium (AGP) that differentiate into adrenal, testes and ovaries. SF-1 is expressed in all three layers of the adrenal cortex, and in the Leydig and Sertoli cells of the testes. It is expressed in embryonic pituitary precursor gonadotrope cells, and in pituitary gonadotropes and the ventro-medial hypothalamus (VMH), Parker KL, et al. (1996); Ikeda Y. (1996). SF-1 has emerged as an important orphan nuclear receptor involved with the transition from embryonic stem cell pluripotency and early embryonic development into organogenesis of the hypothalamic, pituitary, and adrenal-gonadal axis (HPAG), Mullen EM, (2007). Steroidogenic factor 1 is a key coactivater of all genes involved with the formation of primary steroidogenic tissues including steroidogenic enzymes, cholesterol transporters and steroidogenesis-stimulating hormones and their receptors, Wong M, et al. (1997); Val P, et al. (2003). It is required for the development of the urogenital ridge within the embryo and differentiation of the adrenal glands and gonads. SF-1 regulates genes involved in the establishment of hypothalamic-pituitary-adrenal-gonadal axis, Parker KL, et al. (1998). Genes regulated by SF-1 include steroidogenic P-450 enzyme genes CYP11A/CYP11A1 (cholesterol side-chain cleavage enzyme); CYP11B (steroid 11-beta-hydroxylase) and CYP21B/CYP21A2 (steroid 21-hydroxylase); NROB1 (DAX-1/AHCH); STAR (steroidogenic acute regulator); NCOA2 (GRIP-1/TIF2); and NR0B2 (SHP/SHP1). SF-1 is an essential regulator of the sex determination cascade. It coactivates SRY (sex-determining region Y protein) leading to sequential activation of SOX9 and AMH (Mullerian inhibiting substance/MIF/MIS) and INSL3 (RLF/Leydig insulin-like peptide). Mis promotes Mullerian duct regression and RLF controls testis descent. Other factors such as Wilms’ tumor suppressor 1 (WT1) and GATA-4 synergize with SF-1, Parker KL, et al. (1999). The steroidogenic differentiation potential of SF-1 is modulated by DAX-1, Ito M et al. (1997); Swain A, (1998); Nachtigal M, et al. (1998); Parker KL, et al. (2002). SF-1 interacts directly with gene promoter sites on DNA. DAX-1, acting link an adaptor molecule binds to the DNA bound SF-1 and recruits corepressors such as nuclear receptor corepressors (N-CoR), Crawford PA, (1998). Wilms’ tumor 1 (WTI) –KTS isoforms and GATA-4 synergize with SF-1 to promote MIS expression in the sex determination cascade; DAX-1 antagonizes these synergies in vitro, Nachtigal MW, et al. (1998); Tremblay JJ, (2001). Recently, Park SY, et al. (2005) reported that in vivo SF-1 and DAX-1 function cooperatively to mediate somatic cell differentiation within the testes. This raises the idea that SF-1 and DAX-1 interaction may be synergistic or antagonist depending upon cell context and level of differentiation. The ratio of SF-1/DAX-1 is likely important to regulate SF-1 gene expression. Ragazzon B, et al. (2006) recently demonstrated that the ratio of SF-1/DAX-1 proteins is regulated in zona fasciculate (ZF) phenotype adrenocortical tumor cells by adrenocorticotropin (ACTH). Diseases associated with defects or dysregulation of NR5A1 or SF-1 include XY sex reversal, XY genotype expressing a female phenotype, and adrenocortical insufficiency. Knock-out of NR5A1 leads to agenesis of the adrenal and gonads. Sigma offers antibodies, shRNAs and other products useful for the study of the SF-1 gene products. References: Crawford PA, et al. (1998) Nuclear receptor DAX-1 recruits nuclear receptor corepressor N-CoR to steroidogenic factor 1. Mol Cell Biol. 18: 2949-2956. |
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