Steroidogenic factor 1

NR5A1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1YOW, 1ZDT, 4QJR, 4QK4
Identifiers
Aliases	NR5A1, AD4BP, ELP, FTZ1, FTZF1, POF7, SF-1, SF1, SPGF8, SRXY3, hSF-1, nuclear receptor subfamily 5 group A member 1
External IDs	OMIM: 184757 MGI: 1346833 HomoloGene: 3638 GeneCards: NR5A1
Gene ontology Molecular function • transcription regulatory region sequence-specific DNA binding • protein binding • zinc ion binding • lipid binding • RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding • double-stranded DNA binding • enzyme binding • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding • steroid hormone receptor activity • transcription coactivator activity • phospholipid binding • sequence-specific DNA binding • metal ion binding • transcription factor activity, sequence-specific DNA binding • RNA polymerase II distal enhancer sequence-specific DNA binding • DNA binding • chromatin binding Cellular component • nucleoplasm • RNA polymerase II transcription factor complex • nucleus Biological process • regulation of transcription from RNA polymerase II promoter • positive regulation of transcription, DNA-templated • regulation of steroid biosynthetic process • hormone metabolic process • luteinization • reproductive process • hormone-mediated signaling pathway • primary sex determination • tissue development • multicellular organism aging • cell differentiation • maintenance of protein location in nucleus • regulation of transcription, DNA-templated • adrenal gland development • transcription, DNA-templated • female gonad development • steroid hormone mediated signaling pathway • cell-cell signaling • transcription from RNA polymerase II promoter • negative regulation of female gonad development • transcription initiation from RNA polymerase II promoter • male gonad development • positive regulation of male gonad development • positive regulation of transcription from RNA polymerase II promoter • intracellular receptor signaling pathway Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2516	26423
Ensembl	ENSG00000136931	ENSMUSG00000026751
UniProt	Q13285	P33242
RefSeq (mRNA)	NM_004959	NM_139051 NM_001316687
RefSeq (protein)	NP_004950.2 NP_004950.2	NP_620639.1 NP_001303616.1
Location (UCSC)	Chr 9: 124.48 – 124.51 Mb	Chr 2: 38.69 – 38.71 Mb
PubMed search	[1]	[2]
Wikidata

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The steroidogenic factor 1 (SF1) protein controls sexual development in the embryo and at puberty.

SF1 is a member of the nuclear receptor family of intracellular transcription factors and is encoded by the NR5A1 gene (nuclear receptor subfamily 5, group A, member 1).^[3]

Function

SF-1 is a critical regulator of reproduction, regulating the transcription of key genes involved in sexual development and reproduction, most notably StAR and P450_SCC. It can form a transcriptional complex with TDF to up-regulate transcription of the Sox9 gene. Its targets include genes at every level of the hypothalamic-pituitary-gonadal axis, as well as many genes involved in gonadal and adrenal steroidogenesis.^[4]

Clinical significance

Mutations in NR5A1 can produce intersex genitals, absence of puberty, and infertility. It is one cause of arrest of ovarian function in women <40 years of age, which occurs in 1% of all women.

Missense, in-frame and frameshift mutations of NR5A1 have been found in families with 46,XY disorders of sex development, 46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency. 46,XY individuals may have ambiguous or female genitals. Individuals of either karyotype may not enter puberty, although expression of the phenotype, penetrance, fertility, and modes of inheritance can vary. Some mutations are dominant, some are recessive.^[5]

Interactions

Steroidogenic factor 1 has been shown to interact with:

• Beta-catenin^[6][7]
• DAX1^[8][9]
• NRIP1^[10][11]
• SOX9^[12]
• TRERF1.^[13]

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. Taketo M, Parker KL, Howard TA, Tsukiyama T, Wong M, Niwa O, Morton CC, Miron PM, Seldin MF (Jan 1995). "Homologs of Drosophila Fushi-Tarazu factor 1 map to mouse chromosome 2 and human chromosome 9q33". Genomics. 25 (2): 565–7. doi:10.1016/0888-7543(95)80059-U. PMID 7789992.
4. Jameson JL (Dec 2004). "Of mice and men: The tale of steroidogenic factor-1". The Journal of Clinical Endocrinology and Metabolism. 89 (12): 5927–9. doi:10.1210/jc.2004-2047. PMID 15579738.
5. Lourenço D, Brauner R, Lin L, De Perdigo A, Weryha G, Muresan M, Boudjenah R, Guerra-Junior G, Maciel-Guerra AT, Achermann JC, McElreavey K, Bashamboo A (Mar 2009). "Mutations in NR5A1 associated with ovarian insufficiency". The New England Journal of Medicine. 360 (12): 1200–10. doi:10.1056/NEJMoa0806228. PMC 2778147. PMID 19246354.
6. Kennell JA, O'Leary EE, Gummow BM, Hammer GD, MacDougald OA (Aug 2003). "T-cell factor 4N (TCF-4N), a novel isoform of mouse TCF-4, synergizes with beta-catenin to coactivate C/EBPalpha and steroidogenic factor 1 transcription factors". Molecular and Cellular Biology. 23 (15): 5366–75. doi:10.1128/MCB.23.15.5366-5375.2003. PMC 165725. PMID 12861022.
7. Mizusaki H, Kawabe K, Mukai T, Ariyoshi E, Kasahara M, Yoshioka H, Swain A, Morohashi K (Apr 2003). "Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1) gene transcription is regulated by wnt4 in the female developing gonad". Molecular Endocrinology. 17 (4): 507–19. doi:10.1210/me.2002-0362. PMID 12554773.
8. Lopez D, Shea-Eaton W, Sanchez MD, McLean MP (Dec 2001). "DAX-1 represses the high-density lipoprotein receptor through interaction with positive regulators sterol regulatory element-binding protein-1a and steroidogenic factor-1". Endocrinology. 142 (12): 5097–106. doi:10.1210/endo.142.12.8523. PMID 11713202.
9. Sugawara T, Saito M, Fujimoto S (Aug 2000). "Sp1 and SF-1 interact and cooperate in the regulation of human steroidogenic acute regulatory protein gene expression". Endocrinology. 141 (8): 2895–903. doi:10.1210/en.141.8.2895. PMID 10919277.
10. Mellgren G, Børud B, Hoang T, Yri OE, Fladeby C, Lien EA, Lund J (May 2003). "Characterization of receptor-interacting protein RIP140 in the regulation of SF-1 responsive target genes". Molecular and Cellular Endocrinology. 203 (1-2): 91–103. doi:10.1016/S0303-7207(03)00097-2. PMID 12782406.
11. Sugawara T, Abe S, Sakuragi N, Fujimoto Y, Nomura E, Fujieda K, Saito M, Fujimoto S (Aug 2001). "RIP 140 modulates transcription of the steroidogenic acute regulatory protein gene through interactions with both SF-1 and DAX-1". Endocrinology. 142 (8): 3570–7. doi:10.1210/en.142.8.3570. PMID 11459805.
12. De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, Scherer G, Poulat F, Berta P (Nov 1998). "Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene". Molecular and Cellular Biology. 18 (11): 6653–65. doi:10.1128/mcb.18.11.6653. PMC 109250. PMID 9774680.
13. Gizard F, Lavallee B, DeWitte F, Teissier E, Staels B, Hum DW (Oct 2002). "The transcriptional regulating protein of 132 kDa (TReP-132) enhances P450scc gene transcription through interaction with steroidogenic factor-1 in human adrenal cells". The Journal of Biological Chemistry. 277 (42): 39144–55. doi:10.1074/jbc.M205786200. PMID 12101186.

Further reading

• Morohashi KI, Omura T (Dec 1996). "Ad4BP/SF-1, a transcription factor essential for the transcription of steroidogenic cytochrome P450 genes and for the establishment of the reproductive function". FASEB Journal. 10 (14): 1569–77. PMID 9002548.
• Parker KL, Schimmer BP (Jun 1997). "Steroidogenic factor 1: a key determinant of endocrine development and function". Endocrine Reviews. 18 (3): 361–77. doi:10.1210/er.18.3.361. PMID 9183568.
• Achermann JC, Meeks JJ, Jameson JL (Dec 2001). "Phenotypic spectrum of mutations in DAX-1 and SF-1". Molecular and Cellular Endocrinology. 185 (1-2): 17–25. doi:10.1016/S0303-7207(01)00619-0. PMID 11738790.
• Ozisik G, Achermann JC, Jameson JL (Jun 2002). "The role of SF1 in adrenal and reproductive function: insight from naturally occurring mutations in humans". Molecular Genetics and Metabolism. 76 (2): 85–91. doi:10.1016/S1096-7192(02)00032-X. PMID 12083805.
• Jameson JL (Dec 2004). "Of mice and men: The tale of steroidogenic factor-1". The Journal of Clinical Endocrinology and Metabolism. 89 (12): 5927–9. doi:10.1210/jc.2004-2047. PMID 15579738.
• de-Souza BF, Lin L, Achermann JC (Jun 2006). "Steroidogenic factor-1 (SF-1) and its relevance to pediatric endocrinology". Pediatric Endocrinology Reviews. 3 (4): 359–64. doi:10.1159/000094108. PMID 16816804.
• Sadovsky Y, Crawford PA, Woodson KG, Polish JA, Clements MA, Tourtellotte LM, Simburger K, Milbrandt J (Nov 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". Proceedings of the National Academy of Sciences of the United States of America. 92 (24): 10939–43. doi:10.1073/pnas.92.24.10939. PMC 40546. PMID 7479914.
• Sasano H, Shizawa S, Suzuki T, Takayama K, Fukaya T, Morohashi K, Nagura H (Aug 1995). "Ad4BP in the human adrenal cortex and its disorders". The Journal of Clinical Endocrinology and Metabolism. 80 (8): 2378–80. doi:10.1210/jc.80.8.2378. PMID 7629233.
• Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA (Jun 1994). "Nuclear receptor steroidogenic factor 1 regulates the müllerian inhibiting substance gene: a link to the sex determination cascade". Cell. 77 (5): 651–61. doi:10.1016/0092-8674(94)90050-7. PMID 8205615.
• Oba K, Yanase T, Nomura M, Morohashi K, Takayanagi R, Nawata H (Sep 1996). "Structural characterization of human Ad4bp (SF-1) gene". Biochemical and Biophysical Research Communications. 226 (1): 261–7. doi:10.1006/bbrc.1996.1343. PMID 8806624.
• Asa SL, Bamberger AM, Cao B, Wong M, Parker KL, Ezzat S (Jun 1996). "The transcription activator steroidogenic factor-1 is preferentially expressed in the human pituitary gonadotroph". The Journal of Clinical Endocrinology and Metabolism. 81 (6): 2165–70. doi:10.1210/jc.81.6.2165. PMID 8964846.
• Bamberger AM, Ezzat S, Cao B, Wong M, Parker KL, Schulte HM, Asa SL (Jun 1996). "Expression of steroidogenic factor-1 (SF-1) mRNA and protein in the human placenta". Molecular Human Reproduction. 2 (6): 457–61. doi:10.1093/molehr/2.6.457. PMID 9238716.
• Crawford PA, Polish JA, Ganpule G, Sadovsky Y (Oct 1997). "The activation function-2 hexamer of steroidogenic factor-1 is required, but not sufficient for potentiation by SRC-1". Molecular Endocrinology. 11 (11): 1626–35. doi:10.1210/me.11.11.1626. PMID 9328345.
• Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, Ingraham HA (May 1998). "Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression". Cell. 93 (3): 445–54. doi:10.1016/S0092-8674(00)81172-1. PMID 9590178.
• De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, Scherer G, Poulat F, Berta P (Nov 1998). "Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Müllerian hormone gene". Molecular and Cellular Biology. 18 (11): 6653–65. doi:10.1128/mcb.18.11.6653. PMC 109250. PMID 9774680.
• Hammer GD, Krylova I, Zhang Y, Darimont BD, Simpson K, Weigel NL, Ingraham HA (Apr 1999). "Phosphorylation of the nuclear receptor SF-1 modulates cofactor recruitment: integration of hormone signaling in reproduction and stress". Molecular Cell. 3 (4): 521–6. doi:10.1016/S1097-2765(00)80480-3. PMID 10230405.
• Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL (Jun 1999). "A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans". Nature Genetics. 22 (2): 125–6. doi:10.1038/9629. PMID 10369247.

External links

• GeneReviews/NCBI/NIH/UW entry on 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis
• OMIM entries on 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis
• steroidogenic factor 1 at the US National Library of Medicine Medical Subject Headings (MeSH)