TABLE 23

SF-1

Receptor nomenclature NR5A1
Receptor code 4.10.1:OR:5:A1
Other names FTZ-F1, ELP, AD4BP
Molecular information Hs: 461aa, Q13285, chr. 9q331
Rn: 462aa, P50569, chr. 3q112
Mm: 462aa, P33242, chr. 2 B3
DNA binding
   Structure Monomer
   HRE core sequence YCA AGG YCR (half-site)
Partners DAX-1 (physical, functional): inhibits SF-1 transcriptional activation and blocks interaction of WT-1/SF-14,5; WT-1 (physical, functional): enhancement of SF-1 transcriptional activity5; GATA4 (physical, functional)6; Ptx1 (physical, functional): enhancement of SF-1 transcriptional activity7: SOX9 (physical, functional): enhancement of SF-1 transcriptional activity8
Agonists 1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine (64 nM), 1,2-didodecanoyl-sn-glycero-3-phosphoethanolamine (66 nM), 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine (80–120 nM) [EC50]9; phosphatidyl inositols PIP2 and PIP310
Antagonists 1,2-Dilinoleonyl-sn-glycerol-3-phosphocholine (100–300 nM) [IC50]9
Coactivators CREBBP, NCOA1, NCOA2, EDF1, PNRC210,11–15
Corepressors NCOR212
Biologically important isoforms ELP1 {Mm}: differs in its N- and C-terminal domains due to alternative splicing and promoter usage16; ELP2 {Mm}: differs in its N-terminal domain due to alternative splicing and promoter usage16; ELP3 {Mm}: encoded by a slightly longer mRNA due to alternative splicing and promoter usage16
Tissue distribution Developmental: carcinoma cells, urogenital ridge, somatic cells (steroidogenic and nonsteroidogenic), adrenal cortex (but not in the adrenal medulla), ovary and testis (Sertoli and Leydig cells), pituitary (gonadotrope cells), ventromedial hypothalamic nucleus; adult: spleen, eutopic endometriotic tissue, adrenal glands, and gonads (Sertoli and Leydig cells) {Hs, Mm} [Northern blot, in situ hybridization, Western blot, immunohistology]17–19
Functional assays Overexpression of SF-1 in embryonic carcinoma cells results in steroidogenesis (progesterone production) {Mm}20
Main target genes Activated: CYP11A1 {Hs, Mm, Rn},21,22 CYP17 {Hs, Mm, Rn},23,24 MC2R {Hs},25–27 VNN1 {Mm}28
Mutant phenotype Knockout mice lack adrenal glands and gonads, male-to-female sex reversal of the internal and external urogenital tracts, impaired expression of markers in gonadotrophs that regulate steroidogenesis, lack of ventromedial hypothalamic nucleus {Mm} [knockout]29–32; heterozygous mutants exhibit adrenal insufficiency resulting from defects in adrenal development and organization; compensatory mechanisms help to maintain (nearly) normal adrenal function under basal conditions—however; stressful conditions reveal adrenal defects {Mm} [knockout]33–35
Human disease Adrenocortical insufficiency: associated with an Arg255→Leu mutation in the hinge region of the SF-1 receptor36; sex reversal, XY, with adrenal failure: associated with an Arg92→Gln mutation in the DNA-binding domain of the SF-1 receptor33; sex reversal, XY, without adrenal failure: associated with premature termination upstream of sequences encoding the AF-2 domain; this mutated receptor has no transcriptional activity and inhibits the function of the wild type in most cases37

  • aa, amino acids; chr., chromosome; HRE, hormone response element; PIP2, phosphatidylinositol bisphosphate; PIP3, phosphatidylinositol triphosphate; CREBBP, cAMP response element-binding protein binding protein

  • ↵1. Wong M, Ramayya MS, Chrousos GP, Driggers PH, and Parker KL (1996) Cloning and sequence analysis of the human gene encoding steroidogenic factor 1. J Mol Endocrinol 17: 139-147

  • ↵2. Lynch JP, Lala DS, Peluso JJ, Luo W, Parker KL, and White BA (1993) Steroidogenic factor 1, an orphan nuclear receptor, regulates the expression of the rat aromatase gene in gonadal tissues. Mol Endocrinol 7: 776-786

  • ↵3. Ikeda Y, Lala DS, Luo X, Kim E, Moisan MP, and Parker KL (1993) Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression. Mol Endocrinol 7: 852-860

  • ↵4. Ito M, Yu R, and Jameson JL (1997) DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita. Mol Cell Biol 17: 1476-1483

  • ↵5. Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, and Ingraham HA (1998) Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Cell 93: 445-454

  • ↵6. Tremblay JJ and Viger RS (1999) Transcription factor GATA-4 enhances Mullerian inhibiting substance gene transcription through a direct interaction with the nuclear receptor SF-1. Mol Endocrinol 13: 1388-1401

  • ↵7. Tremblay JJ, Marcil A, Gauthier Y, and Drouin J (1999) Ptx1 regulates SF-1 activity by an interaction that mimics the role of the ligand-binding domain. EMBO (Eur Mol Biol Organ) J 18: 3431-3441

  • ↵8. De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck R, Scherer G, Poulat F, and Berta P (1998) Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene. Mol Cell Biol 18: 6653-6665

  • ↵9. Krylova IN, Sablin EP, Moore J, Xu RX, Waitt GM, MacKay JA, Juzumiene D, Bynum JM, Madauss K, Montana V, et al. (2005) Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell 120: 343-355

  • ↵10. Li Y, Choi M, Cavey G, Daugherty J, Suino K, Kovach A, Bingham NC, Kliewer SA, and Xu HE (2005) Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Mol Cell 17: 491-502

  • ↵11. Monte D, DeWitte F, and Hum DW (1998) Regulation of the human P450scc gene by steroidogenic factor 1 is mediated by CBP/p300. J Biol Chem 273: 4585-4591

  • ↵12. Hammer GD, Krylova I, Zhang Y, Darimont BD, Simpson K, Weigel NL, and Ingraham HA (1999) Phosphorylation of the nuclear receptor SF-1 modulates cofactor recruitment: integration of hormone signaling in reproduction and stress. Mol Cell 3: 521-526

  • ↵13. Crawford PA, Polish JA, Ganpule G, and Sadovsky Y (1997) The activation function-2 hexamer of steroidogenic factor-1 is required, but not sufficient for potentiation by SRC-1. Mol Endocrinol 11: 1626-1635

  • ↵14. Kabe Y, Goto M, Shima D, Imai T, Wada T, Morohashi K, Shirakawa M, Hirose S, and Handa H (1999) The role of human MBF1 as a transcriptional coactivator. J Biol Chem 274: 34196-34202

  • ↵15. Zhou D and Chen S (2001) PNRC2 is a 16 kDa coactivator that interacts with nuclear receptors through an SH3-binding motif. Nucleic Acids Res 29: 3939-3948

  • ↵16. Ninomiya Y, Okada M, Kotomura N, Suzuki K, Tsukiyama R, and Niwa O (1995) Genomic organization and isoforms of the mouse ELP gene. J Biochem (Tokyo) 118: 380-389

  • ↵17. Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen WH, Nachtigal MW, Abbud R, Nilson JH, and Parker KL (1994) The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev 8: 2302-2312

  • ↵18. Ikeda Y, Shen WH, Ingraham HA, and Parker KL (1994) Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Mol Endocrinol 8: 654-662

  • ↵19. Shen WH, Moore CC, Ikeda Y, Parker KL, and Ingraham HA (1994) Nuclear receptor steroidogenic factor 1 regulates the mullerian inhibiting substance gene: a link to the sex determination cascade. Cell 77: 651-661

  • ↵20. Crawford PA, Sadovsky Y, and Milbrandt J (1997) Nuclear receptor steroidogenic factor 1 directs embryonic stem cells toward the steroidogenic lineage. Mol Cell Biol 17: 3997-4006

  • ↵21. Takayama K, Morohashi K, Honda S, Hara N, and Omura T (1994) Contribution of Ad4BP, a steroidogenic cell-specific transcription factor, to regulation of the human CYP11A and bovine CYP11B genes through their distal promoters. J Biochem (Tokyo) 116: 193-203

  • ↵22. Hu MC, Hsu NC, Pai CI, Wang CK, and Chung B (2001) Functions of the upstream and proximal steroidogenic factor 1 (SF-1)-binding sites in the CYP11A1 promoter in basal transcription and hormonal response. Mol Endocrinol 15: 812-818

  • ↵23. Bakke M and Lund J (1995) Transcriptional regulation of the bovine CYP17 gene: two nuclear orphan receptors determine activity of cAMP-responsive sequence 2. Endocr Res 21: 509-516

  • ↵24. Jacob AL and Lund J (1998) Mutations in the activation function-2 core domain of steroidogenic factor-1 dominantly suppresses PKA-dependent transactivation of the bovine CYP17 gene. J Biol Chem 273: 13391-13394

  • ↵25. Marchal R, Naville D, Durand P, Begeot M, and Penhoat A (1998) A steroidogenic factor-1 binding element is essential for basal human ACTH receptor gene transcription. Biochem Biophys Res Commun 247: 28-32

  • ↵26. Naville D, Penhoat A, Marchal R, Durand P, and Begeot M (1998) SF-1 and the transcriptional regulation of the human ACTH receptor gene. Endocr Res 24: 391-395

  • ↵27. Naville D, Penhoat A, Durand P, and Begeot M (1999) Three steroidogenic factor-1 binding elements are required for constitutive and cAMP-regulated expression of the human adrenocorticotropin receptor gene. Biochem Biophys Res Commun 255: 28-33

  • ↵28. Wilson MJ, Jeyasuria R, Parker KL, and Koopman P (2005) The transcription factors steroidogenic factor-1 and SOX9 regulate expression of Vanin-1 during mouse testis development. J Biol Chem 280: 5917-5923

  • ↵29. Luo X, Ikeda Y, and Parker KL (1994) A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77: 481-490

  • ↵30. Sadovsky Y, Crawford PA, Woodson KG, Polish KA, Clements MA, Tourtellotte LM, Simburger K, and Milbrandt J (1995) Mice deficient in the orphan receptor steroidogenic factor 1 lack adrenal glands and gonads but express P450 side-chain-cleavage enzyme in the placenta and have normal embryonic serum levels of corticosteroids. Proc Natl Acad Sci USA 92: 10939-10943

  • ↵31. Shinoda K, Lei H, Yoshii H, Nomura M, Nagano M, Shiba H, Sasaki H, Osawa Y, Ninomiya Y, Niwa O, et al. (1995) Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn 204: 22-29

  • ↵32. Zhao L, Bakke M, Krimkevich Y, Cushman LJ, Parlow AF, Camper SA, and Parker KL (2001) Steroidogenic factor 1 (SF1) is essential for pituitary gonadotrope function. Development 128: 147-154

  • ↵33. Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, Gurakan B, and Jameson JL (2002) Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J Clin Endocrinol Metab 87: 1829-1833

  • ↵34. Bland ML, Fowkes RC, and Ingraham HA (2004) Differential requirement for steroidogenic factor-1 gene dosage in adrenal development versus endocrine function. Mol Endocrinol 18: 941-952

  • ↵35. Bland ML, Jamieson CA, Akana SF, Bornstein SR, Eisenhofer G, Dallman MF, and Ingraham HA (2000) Haploinsufficiency of steroidogenic factor-1 in mice disrupts adrenal development leading to an impaired stress response. Proc Natl Acad Sci USA 97: 14488-14493

  • ↵36. Biason-Lauber A and Schoenle EJ (2000) Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency. Am J Hum Genet 67: 1563-1568

  • ↵37. Correa RV, Domenice S, Bingham NC, Billerbeck AE, Rainey WE, Parker KL, and Mendonca BB (2004) A microdeletion in the ligand binding domain of human steroidogenic factor 1 causes XY sex reversal without adrenal insufficiency. J Clin Endocrinol Metab 89: 1767-1772