The Role of Orphan Nuclear Receptor COUP-TPII in Prostate Development and Tumorigenesis

2000 ◽  
Author(s):  
Ge Zhou
Keyword(s):  
Nuclear Receptor ◽  
Orphan Nuclear Receptor ◽  
Prostate Development

The role of the orphan nuclear receptor Rev-Erbα in adipocyte differentiation and function

Biochimie ◽  
2005 ◽  
Vol 87 (1) ◽  
pp. 21-25 ◽  
Author(s):  
S Laitinen ◽  
C Fontaine ◽  
JC Fruchart ◽  
B Staels
Keyword(s):  
Nuclear Receptor ◽  
Adipocyte Differentiation ◽  
Orphan Nuclear Receptor ◽  
And Function

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 HDX-MS reveals structural determinants for RORγ hyperactivation by synthetic agonists

2019 ◽  
Author(s):  
Timothy S. Strutzenberg ◽  
Ruben Garcia-Ordonez ◽  
Scott Novick ◽  
HaJeung Park ◽  
Mi Ra Chang ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Receptor Activation ◽  
Site Directed Mutagenesis ◽  
Orphan Nuclear Receptor ◽  
Chemical Probes ◽  
Structural Determinants ◽  
Synthetic Ligand ◽  
Hdx Ms

ABSTRACTMembers of the nuclear receptor (NR) superfamily regulate both physiological and pathophysiological processes ranging from development and metabolism1 to inflammation2 and cancer3. As ligand-gated transcription factors, synthetic small molecules targeting NRs are often deployed as therapeutics to correct aberrant NR signaling or as chemical probes to explore the role of the receptor in physiology4. However, nearly half of NRs do not have specific cognate ligands or its unclear if they possess ligand dependent activities and these receptors are called orphans. Here we demonstrate that ligand-dependent action of the orphan nuclear receptor RORγ can be defined by selectively disrupting putative endogenous—but not synthetic—ligand binding. Furthermore, the characterization of a library of RORγ modulators reveals that structural dynamics of the receptor assessed by HDX-MS correlate with activity in biochemical and cell-based assays. These findings are corroborated with X-ray co-crystallography and site-directed mutagenesis to collectively reveal the structural determinants of RORγ ligand-dependent activation, critical for designing full agonists for application in cancer immunotherapy. Combined these observations support a model of receptor activation to more accurately describe RORγ pharmacology. Likewise, this ‘bump-and-hole’ inspired approach could be extended to other orphan NRs to explore the ligand-dependent activities that are important for defining pharmacology.

scholarly journals The role of the orphan nuclear receptor COUP-TFII in tumorigenesis

2014 ◽  
Vol 36 (1) ◽  
pp. 32-36 ◽  
Author(s):  
Mafei Xu ◽  
Jun Qin ◽  
Sophia Y Tsai ◽  
Ming-jer Tsai
Keyword(s):  
Nuclear Receptor ◽  
Orphan Nuclear Receptor
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