scholarly journals Multiple Orphan Nuclear Receptors Converge to Regulate Rat P450c17 Gene Transcription: Novel Mechanisms for Orphan Nuclear Receptor Action

1997 ◽  
Vol 11 (7) ◽  
pp. 891-904 ◽  
Author(s):  
Peilin Zhang ◽  
Synthia H. Mellon
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Gene Transcription ◽  
Orphan Nuclear Receptor ◽  
Orphan Nuclear Receptors ◽  
Receptor Action

scholarly journals Spermatogenesis and Testis Development Are Normal in Mice Lacking Testicular Orphan Nuclear Receptor 2

2002 ◽  
Vol 22 (13) ◽  
pp. 4661-4666 ◽  
Author(s):  
Chih-Rong Shyr ◽  
Loretta L. Collins ◽  
Xiao-Min Mu ◽  
Kenneth A. Platt ◽  
Chawnshang Chang
Keyword(s):  
Protein Expression ◽  
Nuclear Receptor ◽  
Expression Patterns ◽  
Orphan Receptor ◽  
Orphan Nuclear Receptor ◽  
Male Mice ◽  
Orphan Nuclear Receptors ◽  
Nuclear Receptor Superfamily ◽  
Testis Development

ABSTRACT Early in vitro cell culture studies suggested that testicular orphan nuclear receptor 2 (TR2), a member of the nuclear receptor superfamily, may play important roles in the control of several pathways including retinoic acids, vitamin D, thyroid hormones, and ciliary neurotrophic factor. Here we report the surprising results showing that mice lacking TR2 are viable and have no serious developmental defects. Male mice lacking TR2 have functional testes, including normal sperm number and motility, and both male and female mice lacking TR2 are fertile. In heterozygous TR2+/− male mice we found that β-galactosidase, the indicator of TR2 protein expression, was first detected at the age of 3 weeks and its expression pattern was restricted mainly in the spermatocytes and round spermatids. These protein expression patterns were further confirmed with Northern blot analysis of TR2 mRNA expression. Together, results from TR2-knockout mice suggest that TR2 may not play essential roles in spermatogenesis and normal testis development, function, and maintenance. Alternatively, the roles of TR2 may be redundant and could be played by other close members of the nuclear receptor superfamily such as testicular orphan receptor 4 (TR4) or unidentified orphan receptors that share many similar functions with TR2. Further studies with double knockouts of both orphan nuclear receptors, TR2 and TR4, may reveal their real physiological roles.

The mouse homolog of the orphan nuclear receptor tailless is expressed in the developing forebrain

Development ◽  
1995 ◽  
Vol 121 (3) ◽  
pp. 839-853 ◽  
Author(s):  
A.P. Monaghan ◽  
E. Grau ◽  
D. Bock ◽  
G. Schutz
Keyword(s):  
Nuclear Receptor ◽  
Binding Domain ◽  
Orphan Nuclear Receptor ◽  
Orphan Nuclear Receptors ◽  
Mouse Homolog ◽  
Recessive Mutations ◽  
Considerable Homology ◽  
Protein Transcription ◽  
Brain Factor ◽  
Nuclear Receptor Subfamily

The Drosophila tailless gene is a member of the orphan nuclear receptor subfamily. In Drosophila, the tailless gene is required for pattern formation in embryonic poles. During development, tailless is activated in the termini of the embryo in response to the torso receptor tyrosine kinase signal transduction cascade. Recessive mutations of tailless result in abnormalities in anterior portions of the head and in all structures posterior to the eighth abdominal segment. Localised expression of tailless is required in combination with a second terminal gene, huckebein, to control the expression of downstream genes. We have isolated a mouse homolog of the Drosophila tailless gene, which shows considerable homology in the DNA-binding domain suggesting that the respective proteins bind similar recognition sequences. Although the ligand-binding domain shows features in common with the tailless ligand domain, it also shares conserved amino acid stretches with other orphan nuclear receptors, the human ovalbumin upstream binding protein transcription factors (hCOUP-TF I and II). We have analysed the expression of taillees in mice, and show that it is specifically localised to the developing forebrain from day 8 p.c. and in dorsal midbrain from day 8.75 p.c. To define the anterior and posterior boundaries of expression, we compared the expression pattern of tailless to those of other forebrain markers, including distal-less (Dlx1), brain factor 1 (BF1), and the orthodenticle genes (Otx1 and Otx2). In addition to the developing forebrain, these genes show dynamic patterns of expression in two structures whose development requires inductive signals from the forebrain: the eye and the nose. These results suggest that the mouse taillees gene may be required to pattern anterior brain differentiation.

scholarly journals Development of Peptide Antagonists for the Androgen Receptor Using Combinatorial Peptide Phage Display

2005 ◽  
Vol 19 (10) ◽  
pp. 2478-2490 ◽  
Author(s):  
Ching-yi Chang ◽  
Jennifer Abdo ◽  
Tanya Hartney ◽  
Donald P. McDonnell
Keyword(s):  
Androgen Receptor ◽  
Phage Display ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Transcriptional Activity ◽  
Binding Pocket ◽  
Orphan Nuclear Receptors ◽  
Nuclear Receptor Coactivator ◽  
Pharmacological Significance ◽  
Peptide Phage Display

Abstract Under the auspices of the Nuclear Receptor Signaling Atlas (NURSA) , we have undertaken to evaluate the feasibility of targeting nuclear receptor-coactivator surfaces for new drug discovery. The underlying objective of this approach is to provide the research community with reagents that can be used to modulate the transcriptional activity of nuclear receptors. Using combinatorial peptide phage display, we have been able to develop peptide antagonists that target specific nuclear receptor (NR)-coactivator binding surfaces. It can be appreciated that reagents of this nature will be of use in the study of orphan nuclear receptors for whom classical ligands have not yet been identified. In addition, because the interaction of coactivators with the receptor is an obligate step for NR transcriptional activity, it is anticipated that peptides that block these interactions will enable the definition of the biological and pharmacological significance of individual NR-coactivator interactions. In this report, we describe the use of this approach to develop antagonists of the androgen receptor by targeting its coactivator-binding pocket and their use to study the coactivator-binding surface of this receptor. Based on our findings, we believe that molecules that function by disrupting the androgen receptor-cofactor interactions will have use in the treatment of prostate cancer.

scholarly journals The Transcriptional Repressor Orphan Nuclear Receptor TLX Is Responsive to Caffeine and Istradefylline

2021 ◽  
Author(s):  
Giuseppe Faudone ◽  
Whitney Kilu ◽  
Xiaomin Ni ◽  
Apirat Chaikuad ◽  
Sridhar Sreeramulu ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Drug Target ◽  
Protein Complexes ◽  
Orphan Nuclear Receptor ◽  
Essential Factor ◽  
Stem Cell Survival ◽  
Functional Understanding ◽  
Repressor Activity

The orphan nuclear receptor TLX is expressed almost exclusively in neural stem cells. TLX acts as an essential factor for neural stem cell survival and is hence considered as a promising drug target in neurodegeneration. However, few studies have characterized the roles of TLX due to a lack of ligands and limited functional understanding. Here, we identify caffeine and istradefylline as TLX ligands that counteract the receptor’s intrinsic repressor activity in reporter gene assays and modulate TLX regulated SIRT1 and p21 expression. Mutagenesis of residues lining a cavity within the TLX ligand binding domain altered activity of these ligands suggesting direct interactions with helix 5. Using istradefylline as a tool compound, we observed ligand-sensitive recruitment of the co-repressor SMRT and heterodimerization of TLX with RXR. Both protein-protein complexes evolve as factors that modulate TLX function and suggest an unprecedented role of TLX in directly repressing other nuclear receptors.

scholarly journals Regulation of Macrophage Inflammatory Gene Expression by the Orphan Nuclear Receptor Nur77

2006 ◽  
Vol 20 (4) ◽  
pp. 786-794 ◽  
Author(s):  
Liming Pei ◽  
Antonio Castrillo ◽  
Peter Tontonoz
Keyword(s):  
Gene Expression ◽  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Liver X Receptor ◽  
Nuclear Hormone Receptor ◽  
Orphan Nuclear Receptor ◽  
Orphan Nuclear Receptors ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

Abstract Members of the nuclear hormone receptor superfamily have emerged as important regulators of macrophage gene expression in inflammation and disease. Previous studies have shown that the lipid-activated receptors peroxisomal proliferator-activated receptor and liver X receptor inhibit nuclear factor-κB (NF-κB) signaling and inflammatory gene expression. We recently identified the NR4A subfamily of orphan nuclear receptors (Nur77/NR4A1, Nurr1/NR4A2, and NOR1/NR4A3) as lipopolysaccharide- and NF-κB-responsive genes in macrophages. However, the role of these transcription factors in macrophage gene expression is unknown. We demonstrate here that, in contrast to peroxisomal proliferator-activated receptor and liver X receptor, the role of NR4A receptors in macrophages is proinflammatory. Retroviral expression of Nur77 in macrophages leads to the transcriptional activation of multiple genes involved in inflammation, apoptosis, and cell cycle control. One particularly interesting Nur77-responsive gene is the inducible kinase IKKi/IKKε, an important component of the NF-κB signaling pathway. The IKKi promoter contains a functional NR4A binding site and is activated by all three NR4A receptors in transient transfection assays. Consistent with the activation of IKKi, expression of Nur77 in macrophages potentiates the induction of inflammatory gene expression in response to lipopolysaccharide. These results identify a new role for NR4A orphan nuclear receptors in the control of macrophage gene expression during inflammation.

scholarly journals Orphan Nuclear Receptor NOR-1 Enhances 3′,5′-Cyclic Adenosine 5′-Monophosphate-Dependent Uncoupling Protein-1 Gene Transcription

2008 ◽  
Vol 22 (5) ◽  
pp. 1057-1064 ◽  
Author(s):  
Naresh Kumar ◽  
Dianxin Liu ◽  
Haibo Wang ◽  
Jacques Robidoux ◽  
Sheila Collins
Keyword(s):  
Nuclear Receptor ◽  
Gene Transcription ◽  
Uncoupling Protein ◽  
Orphan Nuclear Receptor ◽  
Uncoupling Protein 1

Nuclear receptor atlas of female mouse liver parenchymal, endothelial, and Kupffer cells

2013 ◽  
Vol 45 (7) ◽  
pp. 268-275 ◽  
Author(s):  
Zhaosha Li ◽  
J. Kar Kruijt ◽  
Ronald J. van der Sluis ◽  
Theo J. C. Van Berkel ◽  
Menno Hoekstra
Keyword(s):  
Expression Pattern ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Kupffer Cells ◽  
Virgin Female ◽  
Orphan Receptor ◽  
Orphan Nuclear Receptors ◽  
Liver Parenchymal ◽  
Hepatic Expression ◽  
Parenchymal Cells

The liver consists of different cell types that together synchronize crucial roles in liver homeostasis. Since nuclear receptors constitute an important class of drug targets that are involved in a wide variety of physiological processes, we have composed the hepatic cell type-specific expression profile of nuclear receptors to uncover the pharmacological potential of liver-enriched nuclear receptors. Parenchymal liver cells (hepatocytes) and liver endothelial and Kupffer cells were isolated from virgin female C57BL/6 wild-type mice using collagenase perfusion and counterflow centrifugal elutriation. The hepatic expression pattern of 49 nuclear receptors was generated by real-time quantitative PCR using the NUclear Receptor Signaling Atlas (NURSA) program resources. Thirty-six nuclear receptors were expressed in total liver. FXR-α, EAR2, LXR-α, HNF4-α, and CAR were the most abundantly expressed nuclear receptors in liver parenchymal cells. In contrast, NUR77, COUP-TFII, LXR-α/β, FXR-α, and EAR2 were the most highly expressed nuclear receptors in endothelial and Kupffer cells. Interestingly, members of orphan receptor COUP-TF family showed a distinct expression pattern. EAR2 was highly and exclusively expressed in parenchymal cells, while COUP-TFII was moderately and exclusively expressed in endothelial and Kupffer cells. Of interest, the orphan receptor TR4 showed a similar expression pattern as the established lipid sensor PPAR-γ. In conclusion, our study provides the most complete quantitative assessment of the nuclear receptor distribution in liver reported to date. Our gene expression catalog suggests that orphan nuclear receptors such as COUP-TFII, EAR2, and TR4 may be of significant importance as novel targets for pharmaceutical interventions in liver.

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