Naturally-Occurring Mutations in Steroidogenic Factor-1 (Sf-1) Provide Insight into Dose-Dependent Regulation of Gene Transcription by Monomeric Orphan Nuclear Receptors

2002 ◽  
Vol 103 (s47) ◽  
pp. 22P-22P
Author(s):  
John C Achermann ◽  
Gokhan Ozisik ◽  
Masafumi Ito ◽  
Utku A Orun ◽  
Peter C Hindmarsh ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Gene Transcription ◽  
Orphan Nuclear Receptors ◽  
Steroidogenic Factor 1 ◽  
Naturally Occurring ◽  
Dose Dependent ◽  
Insight Into

scholarly journals Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)

2011 ◽  
Vol 54 (7) ◽  
pp. 2266-2281 ◽  
Author(s):  
Richard J. Whitby ◽  
Jozef Stec ◽  
Raymond D. Blind ◽  
Sally Dixon ◽  
Lisa M. Leesnitzer ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Small Molecule ◽  
Orphan Nuclear Receptors ◽  
Steroidogenic Factor 1

scholarly journals The orphan nuclear receptors at their 25-year reunion

2013 ◽  
Vol 51 (3) ◽  
pp. T115-T140 ◽  
Author(s):  
Shannon E Mullican ◽  
Joanna R DiSpirito ◽  
Mitchell A Lazar
Keyword(s):  
Nuclear Receptors ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Steroid Hormone Receptors ◽  
Biological Processes ◽  
Orphan Nuclear Receptors ◽  
Orphan Receptors ◽  
Critical Insight ◽  
Genomic Regions ◽  
Insight Into

The nuclear receptor superfamily includes many receptors, identified based on their similarity to steroid hormone receptors but without a known ligand. The study of how these receptors are diversely regulated to interact with genomic regions to control a plethora of biological processes has provided critical insight into development, physiology, and the molecular pathology of disease. Here we provide a compendium of these so-called orphan receptors and focus on what has been learned about their modes of action, physiological functions, and therapeutic promise.

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

2019 ◽  
Vol 99 (2) ◽  
pp. 1249-1279 ◽  
Author(s):  
Marie-Charlotte Meinsohn ◽  
Olivia E. Smith ◽  
Kalyne Bertolin ◽  
Bruce D. Murphy
Keyword(s):  
Cancer Cells ◽  
Nuclear Receptors ◽  
Leydig Cell ◽  
Dna Sequences ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Specific Cell ◽  
Orphan Nuclear Receptors ◽  
Steroidogenic Factor 1 ◽  
Estrogen Synthesis

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.

Interplay between liganded and orphan nuclear receptors controls reproductive pathways

2000 ◽  
Vol 78 (3) ◽  
pp. 345-358 ◽  
Author(s):  
Raphaël Métivier ◽  
Yves Le Dréan ◽  
Gilles Salbert ◽  
Farzad Pakdel
Keyword(s):  
Estrogen Receptor ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Cell Fate ◽  
Nuclear Receptors ◽  
Gene Transcription ◽  
Transcription Rate ◽  
Orphan Nuclear Receptors ◽  
Estrogen Binding ◽  
Small Hydrophobic

Nuclear receptors are transcription factors that belong to an evolutionary ancient superfamily. These proteins, which are even present in primitive metazoans, are implicated in all levels of cell fate: proliferation, differentiation, and apoptosis. Some of these nuclear receptors behave as ligand-inducible transcription factors, as they have acquired during evolution the ability to bind ligands. This is the case for some proteins that recognize small hydrophobic signaling molecules, and particularly the estrogen receptor (ER or NR3A1), which regulates the target gene's transcription rate under estrogen binding. It is now known that the ER alone regulates the transcription of many genes, such as those implicated in reproductive functions. However, this ER-mediated signaling pathway could be modulated by other transcription factors. Our work has established that two other orphan nuclear receptors (SF-1 or NR5A1 and the COUP-TFs, NR2F1 and NR2F2) can enhance two ER-regulated genes implicated in salmonid reproductive functions: the ER gene itself, and the sGTHIIβ gene. Moreover, some xenoestrogens could disturb these regulations. Therefore, our data contribute to the concept that interplay between nuclear receptors is an important event for the transcriptional regulation of genes controlling cellular functions.Key words: reproduction, estrogen receptor, SF-1, COUP-TFI, gene transcription, xenobiotics.

Human disorders caused by nuclear receptor gene mutations

2003 ◽  
Vol 75 (11-12) ◽  
pp. 1785-1796 ◽  
Author(s):  
J. C. Achermann ◽  
J. L. Jameson
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Receptor Gene ◽  
Critical Role ◽  
Receptor Activation ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Orphan Nuclear Receptors ◽  
Naturally Occurring ◽  
Inactivating Mutations

The identification of naturally occurring nuclear receptor mutations highlights the critical role that many of these transcription factors play in human endocrine development and function. Inactivating mutations in the ligand-dependent nuclear receptors (TRβ, VDR, ERα, GR, MR, AR) are well characterized in patients with conditions such as androgen insensitivity syndrome (AIS) and vitamin D resistance. On the other hand, mutations in TRβ act in a dominant negative manner to cause hormone resistance. Inactivating mutations in orphan nuclear receptors have also been identified (PPARγ2, HNF4α, PNR, NURR1, SF1, DAX1, SHP) and reveal important developmental and metabolic functions for this group of receptors with previously elusive physiologic roles. In addition to loss of function mutations, receptor activation can result from mutations that confer constitutive activity or altered ligand responsiveness to the receptor (MR, AR), or from genetic duplication (DAX1) or the expression of fusion proteins (RARA, PPARγ1). Together, these naturally occurring mutations provide fascinating insight into key structural and functional receptor domains to reveal the diverse role nuclear receptors play in human biology.

Identification of Small Molecule Agonists of the Orphan Nuclear Receptors Liver Receptor Homolog-1 and Steroidogenic Factor-1

2006 ◽  
Vol 49 (23) ◽  
pp. 6652-6655 ◽  
Author(s):  
Richard J. Whitby ◽  
Sally Dixon ◽  
Patrick R. Maloney ◽  
Philippe Delerive ◽  
Bryan J. Goodwin ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Small Molecule ◽  
Orphan Nuclear Receptors ◽  
Steroidogenic Factor 1
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