The orphan nuclear receptor EAR-2 (NR2F6) inhibits hematopoietic cell differentiation and induces myeloid dysplasia in vivo

SHP (short heterodimer partner) is an orphan nuclear receptor that plays an important role in regulating glucose and lipid metabolism. A variety of transcription factors are known to regulate transcription of the PEPCK (phosphoenolpyruvate carboxykinase) gene, which encodes a rate-determining enzyme in hepatic gluconeogenesis. Previous reports identified glucocorticoid receptor and Foxo1 as novel downstream targets regulating SHP inhibition [Borgius, Steffensen, Gustafsson and Treuter (2002) J. Biol. Chem. 277, 49761–49796; Yamagata, Daitoku, Shimamoto, Matsuzaki, Hirota, Ishida and Fukamizu (2004) J. Biol. Chem. 279, 23158–23165]. In the present paper, we show a new molecular mechanism of SHP-mediated inhibition of PEPCK transcription. We also show that the CRE1 (cAMP regulatory element 1; −99 to −76 bp relative to the transcription start site) of the PEPCK promoter is also required for the inhibitory regulation by SHP. SHP repressed C/EBPα (CCAAT/enhancer-binding protein α)-driven transcription of PEPCK through direct interaction with C/EBPα protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPα and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription. Taken together, these results suggest that SHP might regulate a level of hepatic gluconeogenesis driven by C/EBPα activation.

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Orphan Nuclear Receptor NR4A1 Is a Negative Regulator of DHT-Induced Rat Preantral Follicular Growth

Molecular Endocrinology ◽

10.1210/me.2012-1200 ◽

2012 ◽

Vol 26 (12) ◽

pp. 2004-2015 ◽

Cited By ~ 14

Author(s):

Kai Xue ◽

Jia-yin Liu ◽

Bruce D. Murphy ◽

Benjamin K. Tsang

Keyword(s):

Receptor Antagonist ◽

Nuclear Receptor ◽

Mrna Abundance ◽

Orphan Nuclear Receptor ◽

Follicular Growth ◽

Preantral Follicle ◽

Follicle Growth ◽

Preantral Follicles

Abstract Nuclear receptor subfamily 4 group A member1 (NR4A1), an orphan nuclear receptor, is involved in the transcriptional regulation of thecal cell androgen biosynthesis and paracrine factor insulin-like 3 (INSL3) expression. Androgens are known to play an important regulatory role in ovarian follicle growth. Using a chronically androgenized rat model, a preantral follicle culture model and virus-mediated gene delivery, we examined the role and regulation of NR4A1 in the androgenic control of preantral follicular growth. In the present study, Ki67 staining was increased in preantral follicles on ovarian sections from 5α-dihydrotestosterone (DHT)-treated rats. Preantral follicles from DHT-treated rats cultured for 4 d exhibited increased growth and up-regulation of mRNA abundance of G1/S-specific cyclin-D2 (Ccnd2) and FSH receptor (Fshr). Similarly, DHT (1 μm) increased preantral follicular growth and Ccnd2 and Fshr mRNA abundance in vitro. The NR4A1 expression was high in theca cells and was down-regulated by DHT in vivo and in vitro. Forced expression of NR4A1 augmented preantral follicular growth, androstenedione production, and Insl3 expression in vitro. Inhibiting the action of androgen (with androgen receptor antagonist flutamide) or INSL3 (with INSL3 receptor antagonist INSL3 B-chain) reduced NR4A1-induced preantral follicular growth. Furthermore, NR4A1 overexpression enhanced DHT-induced preantral follicular growth, a response attenuated by inhibiting INSL3. In conclusion, DHT promotes preantral follicular growth and attenuates thecal NR4A1 expression in vivo and in vitro. Our findings are consistent with the notion that NR4A1 serves as an important point of negative feedback to minimize the excessive preantral follicle growth in hyperandrogenism.

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Orphan nuclear receptor estrogen-related receptor-β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer

Oncogene ◽

10.1038/sj.onc.1210986 ◽

2007 ◽

Vol 27 (23) ◽

pp. 3313-3328 ◽

Cited By ~ 57

Author(s):

S Yu ◽

Y C Wong ◽

X H Wang ◽

M T Ling ◽

C F Ng ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Nuclear Receptor ◽

Orphan Nuclear Receptor ◽

Prostate Cancer Cells ◽

Potential Therapeutic Target ◽

In Vivo Growth ◽

Estrogen Related Receptor

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Adrenocorticotropic Hormone Regulates the Activities of the Orphan Nuclear Receptor Nur77 through Modulation of Phosphorylation*

Endocrinology ◽

10.1210/endo.138.10.5464 ◽

1997 ◽

Vol 138 (10) ◽

pp. 4138-4146 ◽

Cited By ~ 17

Author(s):

Yanzhuang Li ◽

Lester F. Lau

Keyword(s):

Dna Binding ◽

Nuclear Receptor ◽

Binding Domain ◽

Mitogen Activated Protein Kinase ◽

Dna Binding Domain ◽

Orphan Nuclear Receptor ◽

Expression Of Genes ◽

Acth Treatment ◽

Mitogen Activated Protein

Abstract ACTH treatment of Y1 adrenocortical cells induces the synthesis of Nur77, an orphan nuclear receptor that can act as a potent trans-activator for such genes as 21-hydroxylase (CYP21). Nur77 has thus been proposed to be a mediator of ACTH action in activating the expression of genes that encode steroidogenic enzymes. Here we show that ACTH regulates the activity of Nur77 at the level of phosphorylation. ACTH induces the synthesis of transcriptionally active, DNA-binding Nur77 that is unphosphorylated at Ser354, which resides within the DNA-binding domain. By contrast, the Nur77 population that is constitutively present in Y1 cells is phosphorylated at Ser354 and does not bind DNA. Substitutions of Ser354 with negatively charged amino acids, such as Asp or Glu, dramatically decreased Nur77 DNA-binding and trans-activation activities, whereas mutation to the neutral Ala had no effect. Aside from phosphorylation within the DNA-binding domain, ACTH treatment does not induce modifications in the N- and C-terminal domains of Nur77 that significantly affect activity. Although the specific kinases that phosphorylate Nur77 in vivo are not known, the mitogen-activated protein kinase/pp90RSK pathway is not critical to Nur77 regulation. We propose that ACTH treatment of Y1 cells results in modulation of the activities of both kinases and phosphatases, which, in turn, regulate the activities of such transcription factors as Nur77.

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Reduced Fat Mass in Mice Lacking Orphan Nuclear Receptor Estrogen-Related Receptor α

Molecular and Cellular Biology ◽

10.1128/mcb.23.22.7947-7956.2003 ◽

2003 ◽

Vol 23 (22) ◽

pp. 7947-7956 ◽

Cited By ~ 235

Author(s):

Jiangming Luo ◽

Robert Sladek ◽

Julie Carrier ◽

Jo-Ann Bader ◽

Denis Richard ◽

...

Keyword(s):

Nuclear Receptor ◽

Metabolic Regulation ◽

Hormone Receptors ◽

Target Genes ◽

Serum Biochemistry ◽

Orphan Nuclear Receptor ◽

Steroid Synthesis ◽

Fat Deposits ◽

Estrogen Related Receptor

ABSTRACT The estrogen-related receptor α (ERRα) is an orphan member of the superfamily of nuclear hormone receptors expressed in tissues that preferentially metabolize fatty acids. Despite the molecular characterization of ERRα and identification of target genes, determination of its physiological function has been hampered by the lack of a natural ligand. To further understand the in vivo function of ERRα, we generated and analyzed Estrra-null (ERRα−/−) mutant mice. Here we show that ERRα−/− mice are viable, fertile and display no gross anatomical alterations, with the exception of reduced body weight and peripheral fat deposits. No significant changes in food consumption and energy expenditure or serum biochemistry parameters were observed in the mutant animals. However, the mutant animals are resistant to a high-fat diet-induced obesity. Importantly, DNA microarray analysis of gene expression in adipose tissue demonstrates altered regulation of several enzymes involved in lipid, eicosanoid, and steroid synthesis, suggesting that the loss of ERRα might interfere with other nuclear receptor signaling pathways. In addition, the microarray study shows alteration in the expression of genes regulating adipogenesis as well as energy metabolism. In agreement with these findings, metabolic studies showed reduced lipogenesis in adipose tissues. This study suggests that ERRα functions as a metabolic regulator and that the ERRα−/− mice provide a novel model for the investigation of metabolic regulation by nuclear receptors.

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Orphan Nuclear Receptor ERRγ Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21197148 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7148

Author(s):

Kamalakannan Radhakrishnan ◽

Yong-Hoon Kim ◽

Yoon Seok Jung ◽

Jina Kim ◽

Don-Kyu Kim ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Molecular Mechanism ◽

Nuclear Receptor ◽

Iron Homeostasis ◽

Luciferase Reporter ◽

Orphan Nuclear Receptor ◽

Knock Out

Bone morphogenetic protein 6 (BMP6) is a multifunctional growth factor involved in organ development and homeostasis. BMP6 controls expression of the liver hormone, hepcidin, and thereby plays a crucial role in regulating iron homeostasis. BMP6 gene transcriptional regulation in liver is largely unknown, but would be of great help to externally modulate iron load in pathologic conditions. Here, we describe a detailed molecular mechanism of hepatic BMP6 gene expression by an orphan nuclear receptor, estrogen-related receptor γ (ERRγ), in response to the pro-inflammatory cytokine interleukin 6 (IL-6). Recombinant IL-6 treatment increases hepatic ERRγ and BMP6 expression. Overexpression of ERRγ is sufficient to increase BMP6 gene expression in hepatocytes, suggesting that IL-6 is upstream of ERRγ. In line, knock-down of ERRγ in cell lines or a hepatocyte specific knock-out of ERRγ in mice significantly decreases IL-6 mediated BMP6 expression. Promoter studies show that ERRγ directly binds to the ERR response element (ERRE) in the mouse BMP6 gene promoter and positively regulates BMP6 gene transcription in IL-6 treatment conditions, which is further confirmed by ERRE mutated mBMP6-luciferase reporter assays. Finally, an inverse agonist of ERRγ, GSK5182, markedly inhibits IL-6 induced hepatic BMP6 expression in vitro and in vivo. Taken together, these results reveal a novel molecular mechanism on ERRγ mediated transcriptional regulation of hepatic BMP6 gene expression in response to IL-6.

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The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions

Science Advances ◽

10.1126/sciadv.aav9732 ◽

2019 ◽

Vol 5 (7) ◽

pp. eaav9732 ◽

Cited By ~ 3

Author(s):

Carina Seitz ◽

Juan Huang ◽

Anna-Lena Geiselhöringer ◽

Pamela Galbani-Bianchi ◽

Svenja Michalek ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nuclear Receptor ◽

Transcriptional Control ◽

Intestinal Inflammation ◽

Critical Role ◽

Orphan Nuclear Receptor ◽

Cell Functions

LRH-1 (liver receptor homolog-1/NR5a2) is an orphan nuclear receptor, which regulates glucose and lipid metabolism, as well as intestinal inflammation via the transcriptional control of intestinal glucocorticoid synthesis. Predominantly expressed in epithelial cells, its expression and role in immune cells are presently enigmatic. LRH-1 was found to be induced in immature and mature T lymphocytes upon stimulation. T cell–specific deletion of LRH-1 causes a drastic loss of mature peripheral T cells. LRH-1–depleted CD4+ T cells exert strongly reduced activation-induced proliferation in vitro and in vivo and fail to mount immune responses against model antigens and to induce experimental intestinal inflammation. Similarly, LRH-1–deficient cytotoxic CD8+ T cells fail to control viral infections. This study describes a novel and critical role of LRH-1 in T cell maturation, functions, and immopathologies and proposes LRH-1 as an emerging pharmacological target in the treatment of T cell–mediated inflammatory diseases.

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Orphan Nuclear Receptor GCNF Is Required for the Repression ofPluripotency Genes during Retinoic Acid-Induced EmbryonicStem Cell Differentiation

Molecular and Cellular Biology ◽

10.1128/mcb.25.22.10204.2005 ◽

2005 ◽

Vol 25 (22) ◽

pp. 10204-10204 ◽

Cited By ~ 1

Author(s):

Peili Gu ◽

Damien Le Menuet ◽

Arthur C.-K. Chung ◽

Michael A. Mancini ◽

David A. Wheeler ◽

...

Keyword(s):

Retinoic Acid ◽

Cell Differentiation ◽

Nuclear Receptor ◽

Orphan Nuclear Receptor

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Orphan nuclear receptor TR3/Nur77 regulates VEGF-A–induced angiogenesis through its transcriptional activity

Journal of Experimental Medicine ◽

10.1084/jem.20051523 ◽

2006 ◽

Vol 203 (3) ◽

pp. 719-729 ◽

Cited By ~ 114

Author(s):

Huiyan Zeng ◽

Liuliang Qin ◽

Dezheng Zhao ◽

Xiaolian Tan ◽

Eleanor J. Manseau ◽

...

Keyword(s):

Nuclear Receptor ◽

Transcriptional Activity ◽

Umbilical Vein ◽

Early Response ◽

Tube Formation ◽

Orphan Nuclear Receptor ◽

Dna Binding Domains ◽

Binding Domains ◽

Umbilical Vein Endothelial Cells

Vascular endothelial growth factor (VEGF)-A has essential roles in vasculogenesis and angiogenesis, but the downstream steps and mechanisms by which human VEGF-A acts are incompletely understood. We report here that human VEGF-A exerts much of its angiogenic activity by up-regulating the expression of TR3 (mouse homologue Nur77), an immediate-early response gene and orphan nuclear receptor transcription factor previously implicated in tumor cell, lymphocyte, and neuronal growth and apoptosis. Overexpression of TR3 in human umbilical vein endothelial cells (HUVECs) resulted in VEGF-A–independent proliferation, survival, and induction of several cell cycle genes, whereas expression of antisense TR3 abrogated the response to VEGF-A in these assays and also inhibited tube formation. Nur77 was highly expressed in several types of VEGF-A–dependent pathological angiogenesis in vivo. Also, using a novel endothelial cell-selective retroviral targeting system, overexpression of Nur77 DNA potently induced angiogenesis in the absence of exogenous VEGF-A, whereas Nur77 antisense strongly inhibited VEGF-A–induced angiogenesis. B16F1 melanoma growth and angiogenesis were greatly inhibited in Nur77−/− mice. Mechanistic studies with TR3/Nur77 mutants revealed that TR3/Nur77 exerted most of its effects on cultured HUVECs and its pro-angiogenic effects in vivo, through its transactivation and DNA binding domains (i.e., through transcriptional activity).

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Bile acids inhibit duodenal secretin expression via orphan nuclear receptor small heterodimer partner (SHP)

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00094.2009 ◽

2009 ◽

Vol 297 (1) ◽

pp. G90-G97 ◽

Cited By ~ 9

Author(s):

Ian P. Y. Lam ◽

Leo T. O. Lee ◽

Hueng-Sik Choi ◽

Gianfranco Alpini ◽

Billy K. C. Chow

Keyword(s):

Gene Expression ◽

Bile Acids ◽

Nuclear Receptor ◽

Target Genes ◽

In Vivo Studies ◽

Control Group ◽

Orphan Nuclear Receptor ◽

Small Heterodimer Partner

Small heterodimer partner (SHP) is an orphan nuclear receptor in which gene expression can be upregulated by bile acids. It regulates its target genes by repressing the transcriptional activities of other nuclear receptors including NeuroD, which has been shown to regulate secretin gene expression. Here, we evaluated the regulation on duodenal secretin gene expression by SHP and selected bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA). In vitro treatment of CDCA or fexaramine elevated the SHP transcript level and occupancy on secretin promoter. The increase in the SHP level, induced by bile acid treatment or overexpression, reduced secretin gene expression, whereas this gene inhibitory effect was reversed by silencing of endogenous SHP. In in vivo studies, double-immunofluorescence staining demonstrated the coexpression of secretin and SHP in mouse duodenum. Feeding mice with 1% CA-enriched rodent chow resulted in upregulation of SHP and a concomitant decrease in secretin transcript and protein levels in duodenum compared with the control group fed with normal chow. A diet enriched with 5% cholestyramine led to a decrease in SHP level and a corresponding increase in secretin expression. Overall, this study showed that bile acids via SHP inhibit duodenal secretin gene expression. Because secretin is a key hormone that stimulates bile flow in cholangiocytes, this pathway thus provides a novel means to modulate secretin-stimulated choleresis in response to intraduodenal bile acids.

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