Steroidogenic factor-1: a key regulator of gonadotroph gene expression

Fowkes, Robert C.; Burrin, Jacky M.

doi:10.1677/joe.0.1770345

Cited by 12 publications

(4 citation statements)

References 51 publications

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“…Many 46,XY patients with NR5A1 mutations are born with severely undervirilized genitalia, although the clinical presentation may vary considerably (reviewed in (14-16)). In addition, Sf-1 acts as an inductor of gonadotrophin expression, and pituitary-specific Sf-1 knockout mice develop hypogonadotropic hypogonadism and sexual infantilism, due to the absent expression of LH and FSH (18,24,25). In contrast to this, hypergonadotropic hypogonadism is documented in many patients with NR5A1 mutations (6-9), suggesting functional differences of SF-1 in humans compared with mice with regard to gonadotropin expression and puberty.…”

Section: Discussionmentioning

confidence: 99%

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

Cools

Hoebeke

Wolffenbuttel

et al. 2012

European Journal of Endocrinology

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Objective: Most patients with NR5A1 (SF-1) mutations and poor virilization at birth are sex-assigned female and receive early gonadectomy. Although studies in pituitary-specific Sf-1 knockout mice suggest hypogonadotropic hypogonadism, little is known about endocrine function at puberty and on germ cell tumor risk in patients with SF-1 mutations. This study reports on the natural course during puberty and on gonadal histology in two adolescents with SF-1 mutations and predominantly female phenotype at birth. Design and methods: Clinical and hormonal data and histopathological studies are reported in one male and one female adolescent with, respectively, a nonsense mutation (c.9TOA, p.Tyr3X) and a deletion of the first two coding exons (NCBI36/hg18 Chr9:g.(126306276-126307705)_(126303229-126302828)del) of NR5A1, both predicted to fully disrupt gene function. Results: LH and testosterone concentrations were in the normal male range, virilization was disproportionate to the neonatal phenotype. In the girl, gonadectomy at 13 years revealed incomplete spermatogenesis and bilateral precursor lesions of testicular carcinoma in situ. In the boy, at the age of 12, numerous germ cells without signs of malignancy were present in bilateral testicular biopsy specimen. Conclusions: In SF-1 mutations, the neonatal phenotype poorly predicts virilization at puberty. Even in poorly virilized cases at birth, male gender assignment may allow spontaneous puberty without signs of hypogonadotropic hypogonadism, and possibly fertility. Patients with SF-1 mutations are at increased risk for malignant germ cell tumors. In case of preserved gonads, early orchidopexy and germ cell tumor screening is warranted. The finding of premalignant and/or malignant changes should prompt gonadectomy or possibly irradiation.

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Section: Discussionmentioning

confidence: 99%

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

Cools

Hoebeke

Wolffenbuttel

et al. 2012

European Journal of Endocrinology

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“…The promoter regions of the common ␣-subunit and the subunits specific to the gonadotropic hormones, FSH␤ and LH␤, display the SF-1/LRH-1 response element, indicating direct regulation by the NR5A receptors (81). Mutation of this site eliminated LH␤ promoter activity (135).…”

Section: B Gonadotropin Synthesis and Releasementioning

confidence: 99%

The Orphan Nuclear Receptors Steroidogenic Factor-1 and Liver Receptor Homolog-1: Structure, Regulation, and Essential Roles in Mammalian Reproduction

Meinsohn

Smith

Bertolin

et al. 2019

Physiological Reviews

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Nuclear receptors are intracellular proteins that act as transcription factors. Proteins with classic nuclear receptor domain structure lacking identified signaling ligands are designated orphan nuclear receptors. Two of these, steroidogenic factor-1 (NR5A1, also known as SF-1) and liver receptor homolog-1 (NR5A2, also known as LRH-1), bind to the same DNA sequences, with different and nonoverlapping effects on targets. Endogenous regulation of both is achieved predominantly by cofactor interactions. SF-1 is expressed primarily in steroidogenic tissues, LRH-1 in tissues of endodermal origin and the gonads. Both receptors modulate cholesterol homeostasis, steroidogenesis, tissue-specific cell proliferation, and stem cell pluripotency. LRH-1 is essential for development beyond gastrulation and SF-1 for genesis of the adrenal, sexual differentiation, and Leydig cell function. Ovary-specific depletion of SF-1 disrupts follicle development, while LRH-1 depletion prevents ovulation, cumulus expansion, and luteinization. Uterine depletion of LRH-1 compromises decidualization and pregnancy. In humans, SF-1 is present in endometriotic tissue, where it regulates estrogen synthesis. SF-1 is underexpressed in ovarian cancer cells and overexpressed in Leydig cell tumors. In breast cancer cells, proliferation, migration and invasion, and chemotherapy resistance are regulated by LRH-1. In conclusion, the NR5A orphan nuclear receptors are nonredundant factors that are crucial regulators of a panoply of biological processes, across multiple reproductive tissues.

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“…SF1 is a nuclear receptor (NR) that plays a key role not only in steroidogenesis but also in endocrine development and sex differentiation (6,25,32,73,82,83). Targeted disruption of SF1 in mice resulted in adrenal and gonadal agenesis, absence of the ventromedial hypothalamic nucleus, and impaired expression of pituitary gonadotropins (42,69,118).…”

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confidence: 99%

Cyclic AMP-Stimulated Interaction between Steroidogenic Factor 1 and Diacylglycerol Kinase θ Facilitates Induction of CYP17

Urs

Allegood

et al. 2007

Molecular and Cellular Biology

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In the human adrenal cortex, adrenocorticotropin (ACTH) activates CYP17 transcription by promoting the binding of the nuclear receptor steroidogenic factor 1 (SF1) (Ad4BP, NR5A1) to the promoter. We recently found that sphingosine is an antagonist for SF1 and inhibits cyclic AMP (cAMP)-dependent CYP17 gene transcription. The aim of the current study was to identify phospholipids that bind to SF1 and to characterize the mechanism by which ACTH/cAMP regulates the biosynthesis of this molecule(s). Using tandem mass spectrometry, we show that in H295R human adrenocortical cells, SF1 is bound to phosphatidic acid (PA). Activation of the ACTH/cAMP signal transduction cascade rapidly increases nuclear diacylglycerol kinase (DGK) activity and PA production. PA stimulates SF1-dependent transcription of CYP17 reporter plasmids, promotes coactivator recruitment, and induces the mRNA expression of CYP17 and several other steroidogenic genes. Inhibition of DGK activity attenuates the binding of SF1 to the CYP17 promoter, and silencing of DGK-expression inhibits cAMP-dependent CYP17 transcription. LXXLL motifs in DGK-mediate a direct interaction of SF1 with the kinase and may facilitate binding of PA to the receptor. We conclude that ACTH/cAMP stimulates PA production in the nucleus of H295R cells and that this increase in PA concentrations facilitates CYP17 induction.In the zonae fasciculata and reticularis of the human adrenal cortex, the biosynthesis of steroid hormones is activated by the peptide hormone adrenocorticotropin (ACTH), which activates a cyclic AMP (cAMP)-dependent signal transduction cascade, resulting in a rapid increase in hormone production and a sustained induction of the expression of steroidogenic genes. We have shown that cAMP-stimulated transcription of one of these steroidogenic genes, CYP17, is mediated by the binding of a complex containing steroidogenic factor 1 (SF1), p54 nrb , and polypyrimidine-tract-binding protein-associated splicing factor to the CYP17 promoter (93). The binding of this complex is concomitant with the cyclical association of several coregulatory proteins, including GCN5, steroid receptor coactivator 1, and ATPase-dependent chromatin remodeling factors (16).An integral regulator of CYP17 and most other steroidogenic genes in the adrenal cortex and gonads is SF1 (5, 94). SF1 is a nuclear receptor (NR) that plays a key role not only in steroidogenesis but also in endocrine development and sex differentiation (6,25,32,73,82,83). Targeted disruption of SF1 in mice resulted in adrenal and gonadal agenesis, absence of the ventromedial hypothalamic nucleus, and impaired expression of pituitary gonadotropins (42,69,118). The ability of SF1 to transactivate target genes has been shown to be regulated by phosphorylation (19,31,95,97), sumoylation (12, 54), acetylation (11,44,46), and protein-protein interactions (7,16,61,62,75,93,115,120).Recently we identified sphingosine (SPH) as an endogenous ligand for SF1 (109). SPH is bound to the receptor under basal conditions, and cAMP treatme...

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Steroidogenic factor-1: a key regulator of gonadotroph gene expression

Cited by 12 publications

References 51 publications

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

Pubertal androgenization and gonadal histology in two 46,XY adolescents with NR5A1 mutations and predominantly female phenotype at birth

The Orphan Nuclear Receptors Steroidogenic Factor-1 and Liver Receptor Homolog-1: Structure, Regulation, and Essential Roles in Mammalian Reproduction

Cyclic AMP-Stimulated Interaction between Steroidogenic Factor 1 and Diacylglycerol Kinase θ Facilitates Induction of CYP17

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