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Target not currently curated in GtoImmuPdb
Target id: 632
Nomenclature: Steroidogenic factor 1
Systematic Nomenclature: NR5A1
Gene and Protein Information  |
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| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 461 | 9q33.3 | NR5A1 | nuclear receptor subfamily 5 group A member 1 | 36 |
| Mouse | 462 | 2 24.42 cM | Nr5a1 | nuclear receptor subfamily 5, group A, member 1 | 12 |
| Rat | 462 | 3q12 | Nr5a1 | nuclear receptor subfamily 5, group A, member 1 | 21 |
| Previous and Unofficial Names |
| ELP | FTZ1 | SF-1 | adrenal 4-binding protein | steroid hormone receptor Ad4BP | FTZF1 | fushi tarazu factor homolog 1 | STF-1 | nuclear receptor subfamily 5, group A, member 1 | nuclear receptor subfamily 5 |
| Database Links |
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| Alphafold | Q13285 (Hs), P33242 (Mm), P50569 (Rn) |
| CATH/Gene3D | 3.30.50.10 |
| ChEMBL Target | CHEMBL4666 (Hs), CHEMBL1764943 (Mm) |
| Ensembl Gene | ENSG00000136931 (Hs), ENSMUSG00000026751 (Mm), ENSRNOG00000012682 (Rn) |
| Entrez Gene | 2516 (Hs), 26423 (Mm), 83826 (Rn) |
| Human Protein Atlas | ENSG00000136931 (Hs) |
| KEGG Gene | hsa:2516 (Hs), mmu:26423 (Mm), rno:83826 (Rn) |
| OMIM | 184757 (Hs) |
| Orphanet | ORPHA168312 (Hs) |
| Pharos | Q13285 (Hs) |
| RefSeq Nucleotide | NM_004959 (Hs), NM_139051 (Mm), NM_001191099 (Rn) |
| RefSeq Protein | NP_004950 (Hs), NP_620639 (Mm), NP_001178028 (Rn) |
| UniProtKB | Q13285 (Hs), P33242 (Mm), P50569 (Rn) |
| Wikipedia | NR5A1 (Hs) |
| Selected 3D Structures |
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| Natural/Endogenous Ligands |
| Comments: Orphan |
Download all structure-activity data for this target as a CSV file 
| Agonists |
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||
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| DNA Binding |
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| DNA Binding Comments | |||||||
| YCA AGG YCR binding element is also known as the steroidogenic factor binding element (SFRE). | |||||||
| Co-binding Partners |
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| Name | Interaction | Effect | Reference |
| DAX1 | Physical, Functional | DAX1 inhibits SF-1 transcriptional activation and blocks SF-1:WT-1 interaction and thereby the WT-1/SF1 synergism. | 15,24 |
| WT1 | Physical, Functional | WT1 (Wilms Tumor Gene)-KTS isoforms associate and synergize with SF-1 to promote SF-& transcriptional activity. Interestingly, WT1 missense mutations, associated with male pseudo-hermaphroditism in Denys-Drash syndrome, fail to synergize with SF-1. | 24 |
| GATA-4 | Physical, Functional | GATA-4/SF-1 synergize as a result of a direct protein-protein interaction mediated through the zinc finger region of GATA-4. Remarkably, synergy between GATA-4 and SF-1 on a variety of different SF-1 targets did not absolutely require GATA binding to DNA. | 33 |
| Ptx1 | Physical, Functional | The interaction between the C-terminus of Ptx1 and the N-terminal half of SF-1 results in SF-1 transcriptional activity enhancement. | 32 |
| SOX9 | Physical, Functional | SOX9 and SF-1 interact directly via the SOX9 DNA-binding domain and the SF-1 C-terminal region, respectively. This interaction results in the enhancement of SF-1 transcriptional activity. | 9 |
| Main Co-regulators |
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| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| CREBBP | Co-activator | No | No | Yes | 23 | |
| NCOA1 | Co-activator | No | No | Yes | 7 | |
| EDF1 | Co-activator | No | No | Yes | 17 | |
| NCOR2 | Co-repressor | No | No | No | 10 | |
| NCOA2 | Co-activator | No | Yes | Yes | Three studies proposed that phospholipid may be bona fide ligand for the SF-1 receptor, but ligand occupancy does not alter the structure of critical residues within the AF2 cleft. | 10,19 |
| PNRC2 | Co-activator | No | No | Yes | Using the yeast two-hybrid assay, the region amino acids 85-139 of PNRC2 was found to be responsible for the interaction with nuclear receptors. This region contains an SH3 domain-binding motif (SEPPSPS) and an NR box-like sequence (LKTLL). A mutagenesis study has shown that the SH3 domain-binding motif is important for PNRC2 to interact with nuclear receptors | 37 |
| Main Target Genes |
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| Name | Species | Effect | Technique | Comments | References |
| CYP17A1 | Human | Activated | Transient transfection, EMSA, Other | 2,16 | |
| CYP11A1 | Human | Activated | Transient transfection, EMSA, Other | Evidence indicates that this is also true for the mouse and rat | 11,31 |
| MC2R | Human | Activated | Transient transfection, EMSA | 22,25-26 | |
| Vann1 | Mouse | Activated | Transient transfection, EMSA, Footprint | 35 | |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| The mouse SF-1 gene generate two isoforms, ELP and SF-1 that have different expression patterns. ELP was shown to be expressed in embryonic carcinoma cells and to be down-regulated during their differentiation. In mouse ELP was not found from E8 to adult suggesting it is only expressed in early embryos. In contrast SF-1 was expressed from E9 in the urogenital ridge, in somatic cells that are both steroidogenc and non-steroidogenic. In addition SF-1 is found in the adrenal cortex early, but is not found in the adrenal medulla. Interestingly, sexually dimorphic expression of SF-1 is detected. When testicular cords are forming in males a strong and diffuse SF-1 expression can be observed. SF-1 is expressed in both the Sertoli and Leydig cells. In contrast in the ovary SF-1 transcripts disappear between E13.5 to E16.5 and then reappear during late development (E18) with expression increasing post-natally. These data have led to the suggestion that in addition to a role in steroidogenesis SF-1 was playing a role in male sexual differentiation. In the neuroendocrine system, expression of SF-1 is noted in the pituitary as well as in the ventromedial hypothalamic nucleus. In the pituitary expression is restreicted to the gonadotrope cells. Isolated reports have noted expression in the spleen and in human eutopic endometrioctic tissue. In human transcripts at 3.5-4 kb were observed in the adrenals and gonads as well as transcripts at 4.4 kb and 8 kb. An expression of human SF-1 in Sertoli cells as well as in steroidogenic Leydig cells was observed, similar to the mouse pattern. | ||||||||
| Functional Assays
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| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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| Biologically Significant Variants
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1. Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, Gurakan B, 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 (4): 1829-33. [PMID:11932325]
2. Bakke M, Lund J. (1995) Transcriptional regulation of the bovine CYP17 gene: two nuclear orphan receptors determine activity of cAMP-responsive sequence 2. Endocr Res, 21 (1-2): 509-16. [PMID:7588416]
3. Biason-Lauber A, 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 (6): 1563-8. [PMID:11038323]
4. Bland ML, Fowkes RC, Ingraham HA. (2004) Differential requirement for steroidogenic factor-1 gene dosage in adrenal development versus endocrine function. Mol Endocrinol, 18 (4): 941-52. [PMID:14726490]
5. Bland ML, Jamieson CA, Akana SF, Bornstein SR, Eisenhofer G, Dallman MF, 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 (26): 14488-93. [PMID:11121051]
6. Correa RV, Domenice S, Bingham NC, Billerbeck AE, Rainey WE, Parker KL, 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 (4): 1767-72. [PMID:15070943]
7. Crawford PA, Polish JA, Ganpule G, 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 (11): 1626-35. [PMID:9328345]
8. Crawford PA, Sadovsky Y, Milbrandt J. (1997) Nuclear receptor steroidogenic factor 1 directs embryonic stem cells toward the steroidogenic lineage. Mol Cell Biol, 17 (7): 3997-4006. [PMID:9199334]
9. De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, Scherer G, Poulat F, Berta P. (1998) Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene. Mol Cell Biol, 18 (11): 6653-65. [PMID:9774680]
10. Hammer GD, Krylova I, Zhang Y, Darimont BD, Simpson K, Weigel NL, Ingraham HA. (1999) Phosphorylation of the nuclear receptor SF-1 modulates cofactor recruitment: integration of hormone signaling in reproduction and stress. Mol Cell, 3 (4): 521-6. [PMID:10230405]
11. Hu MC, Hsu NC, Pai CI, Wang CK, Chung Bc. (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 (5): 812-8. [PMID:11328860]
12. Ikeda Y, Lala DS, Luo X, Kim E, Moisan MP, Parker KL. (1993) Characterization of the mouse FTZ-F1 gene, which encodes a key regulator of steroid hydroxylase gene expression. Mol Endocrinol, 7 (7): 852-60. [PMID:8413309]
13. Ikeda Y, Shen WH, Ingraham HA, Parker KL. (1994) Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Mol Endocrinol, 8 (5): 654-62. [PMID:8058073]
14. Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen WH, Nachtigal MW, Abbud R, Nilson JH, Parker KL. (1994) The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev, 8 (19): 2302-12. [PMID:7958897]
15. Ito M, Yu R, 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 (3): 1476-83. [PMID:9032275]
16. Jacob AL, 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 (22): 13391-4. [PMID:9593668]
17. Kabe Y, Goto M, Shima D, Imai T, Wada T, Morohashi K, Shirakawa M, Hirose S, Handa H. (1999) The role of human MBF1 as a transcriptional coactivator. J Biol Chem, 274 (48): 34196-202. [PMID:10567391]
18. Krylova IN, Sablin EP, Moore J, Xu RX, Waitt GM, MacKay JA, Juzumiene D, Bynum JM, Madauss K, Montana V, Lebedeva L, Suzawa M, Williams JD, Williams SP, Guy RK, Thornton JW, Fletterick RJ, Willson TM, Ingraham HA. (2005) Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell, 120 (3): 343-55. [PMID:15707893]
19. Li Y, Choi M, Cavey G, Daugherty J, Suino K, Kovach A, Bingham NC, Kliewer SA, Xu HE. (2005) Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Mol Cell, 17 (4): 491-502. [PMID:15721253]
20. Luo X, Ikeda Y, Parker KL. (1994) A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell, 77 (4): 481-90. [PMID:8187173]
21. Lynch JP, Lala DS, Peluso JJ, Luo W, Parker KL, White BA. (1993) Steroidogenic factor 1, an orphan nuclear receptor, regulates the expression of the rat aromatase gene in gonadal tissues. Mol Endocrinol, 7 (6): 776-86. [PMID:8395654]
22. Marchal R, Naville D, Durand P, Begeot M, Penhoat A. (1998) A steroidogenic factor-1 binding element is essential for basal human ACTH receptor gene transcription. Biochem Biophys Res Commun, 247 (1): 28-32. [PMID:9636648]
23. Monté D, DeWitte F, Hum DW. (1998) Regulation of the human P450scc gene by steroidogenic factor 1 is mediated by CBP/p300. J Biol Chem, 273 (8): 4585-91. [PMID:9468515]
24. Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, Ingraham HA. (1998) Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Cell, 93 (3): 445-54. [PMID:9590178]
25. Naville D, Penhoat A, Durand P, 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 (1): 28-33. [PMID:10082650]
26. Naville D, Penhoat A, Marchal R, Durand P, Bégeot M. (1998) SF-1 and the transcriptional regulation of the human ACTH receptor gene. Endocr Res, 24 (3-4): 391-5. [PMID:9888512]
27. Ninomiya Y, Okada M, Kotomura N, Suzuki K, Tsukiyama T, Niwa O. (1995) Genomic organization and isoforms of the mouse ELP gene. J Biochem, 118 (2): 380-9. [PMID:8543574]
28. Sadovsky Y, Crawford PA, Woodson KG, Polish JA, Clements MA, Tourtellotte LM, Simburger K, 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 (24): 10939-43. [PMID:7479914]
29. Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA. (1994) Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade. Cell, 77 (5): 651-61. [PMID:8205615]
30. Shinoda K, Lei H, Yoshii H, Nomura M, Nagano M, Shiba H, Sasaki H, Osawa Y, Ninomiya Y, Niwa O. (1995) Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn, 204 (1): 22-9. [PMID:8563022]
31. Takayama K, Morohashi K, Honda S, Hara N, 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, 116 (1): 193-203. [PMID:7798178]
32. Tremblay JJ, Marcil A, Gauthier Y, Drouin J. (1999) Ptx1 regulates SF-1 activity by an interaction that mimics the role of the ligand-binding domain. EMBO J, 18 (12): 3431-41. [PMID:10369682]
33. Tremblay JJ, Viger RS. (1999) Transcription factor GATA-4 enhances Müllerian inhibiting substance gene transcription through a direct interaction with the nuclear receptor SF-1. Mol Endocrinol, 13 (8): 1388-401. [PMID:10446911]
34. Whitby RJ, Stec J, Blind RD, Dixon S, Leesnitzer LM, Orband-Miller LA, Williams SP, Willson TM, Xu R, Zuercher WJ et al.. (2011) Small molecule agonists of the orphan nuclear receptors steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homologue-1 (LRH-1, NR5A2). J Med Chem, 54 (7): 2266-81. [PMID:21391689]
35. Wilson MJ, Jeyasuria P, Parker KL, Koopman P. (2005) The transcription factors steroidogenic factor-1 and SOX9 regulate expression of Vanin-1 during mouse testis development. J Biol Chem, 280 (7): 5917-23. [PMID:15590666]
36. Wong M, Ramayya MS, Chrousos GP, Driggers PH, Parker KL. (1996) Cloning and sequence analysis of the human gene encoding steroidogenic factor 1. J Mol Endocrinol, 17 (2): 139-47. [PMID:8938589]
37. Zhou D, Chen S. (2001) PNRC2 is a 16 kDa coactivator that interacts with nuclear receptors through an SH3-binding motif. Nucleic Acids Res, 29 (19): 3939-48. [PMID:11574675]
5A. Fushi tarazu F1-like receptors: Steroidogenic factor 1. Last modified on 10/09/2019. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=632.
