scholarly journals Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1373 ◽  
Author(s):  
Herring ◽  
Elison ◽  
Tessem
Keyword(s):  
Transcription Factors ◽  
Family Member ◽  
Nuclear Receptors ◽  
Hormone Receptors ◽  
Cellular Proliferation ◽  
Nuclear Hormone Receptors ◽  
Fuel Utilization ◽  
Orphan Nuclear Receptors ◽  
Tissue Specific ◽  
Specific Effects

The Nr4a family of nuclear hormone receptors is composed of three members—Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization.

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 Minireview: Genomics Versus Orphan Nuclear Receptors—A Half-Time Report

2002 ◽  
Vol 16 (6) ◽  
pp. 1135-1144
Author(s):  
Timothy M. Willson ◽  
John T. Moore
Keyword(s):  
Nuclear Receptors ◽  
Drug Targets ◽  
Hormone Receptors ◽  
Receptor Gene ◽  
Orphan Nuclear Receptors ◽  
Orphan Receptors ◽  
Genomic Technologies ◽  
Full Complement ◽  
And Function ◽  
The Impact

Abstract Following the successful cloning of the orphan nuclear receptors during the 1990s we entered the 21st century with knowledge of the full complement of human nuclear receptors. Many of these proteins are ligand-activated transcription factors that act as the cognate receptors for steroid, retinoid, and thyroid hormones. In addition to these well characterized endocrine hormone receptors, there are a large number of orphan receptors of which less is known about the nature and function of their ligands. The task of deciphering the physiological function of these orphan receptors has been aided by a new generation of genomic technologies. Through application of chemical, structural, and functional genomics, several orphan nuclear receptors have emerged as pharmaceutical drug targets for the treatment of important human diseases. The significant progress that has been made in the functional analysis of more than half of the nuclear receptor gene family provides an opportunity to review the impact of genomics in this endeavor.

scholarly journals Small-Molecule Hormones: Molecular Mechanisms of Action

2013 ◽  
Vol 2013 ◽  
pp. 1-21 ◽  
Author(s):  
Monika Puzianowska-Kuznicka ◽  
Eliza Pawlik-Pachucka ◽  
Magdalena Owczarz ◽  
Monika Budzińska ◽  
Jacek Polosak
Keyword(s):  
Transcription Factors ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
Hormone Receptors ◽  
Target Genes ◽  
Direct Interaction ◽  
Nuclear Hormone Receptors ◽  
Membrane Phospholipids ◽  
Basal Transcription Factors ◽  
Hormonal Stimulus

Small-molecule hormones play crucial roles in the development and in the maintenance of an adult mammalian organism. On the molecular level, they regulate a plethora of biological pathways. Part of their actions depends on their transcription-regulating properties, exerted by highly specific nuclear receptors which are hormone-dependent transcription factors. Nuclear hormone receptors interact with coactivators, corepressors, basal transcription factors, and other transcription factors in order to modulate the activity of target genes in a manner that is dependent on tissue, age and developmental and pathophysiological states. The biological effect of this mechanism becomes apparent not earlier than 30–60 minutes after hormonal stimulus. In addition, small-molecule hormones modify the function of the cell by a number of nongenomic mechanisms, involving interaction with proteins localized in the plasma membrane, in the cytoplasm, as well as with proteins localized in other cellular membranes and in nonnuclear cellular compartments. The identity of such proteins is still under investigation; however, it seems that extranuclear fractions of nuclear hormone receptors commonly serve this function. A direct interaction of small-molecule hormones with membrane phospholipids and with mRNA is also postulated. In these mechanisms, the reaction to hormonal stimulus appears within seconds or minutes.

scholarly journals Orphan nuclear receptors in breast cancer pathogenesis and therapeutic response

2010 ◽  
Vol 17 (3) ◽  
pp. R213-R231 ◽  
Author(s):  
Rebecca B Riggins ◽  
Mary M Mazzotta ◽  
Omar Z Maniya ◽  
Robert Clarke
Keyword(s):  
Breast Cancer ◽  
Transcription Factors ◽  
Nuclear Receptors ◽  
Large Family ◽  
Orphan Receptor ◽  
Orphan Nuclear Receptors ◽  
Cancer Pathogenesis ◽  
Upstream Promoter ◽  
Carboxy Terminal ◽  
Gland Development

Nuclear receptors comprise a large family of highly conserved transcription factors that regulate many key processes in normal and neoplastic tissues. Most nuclear receptors share a common, highly conserved domain structure that includes a carboxy-terminal ligand-binding domain. However, a subgroup of this gene family is known as the orphan nuclear receptors because to date there are no known natural ligands that regulate their activity. Many of the 25 nuclear receptors classified as orphan play critical roles in embryonic development, metabolism, and the regulation of circadian rhythm. Here, we review the emerging role(s) of orphan nuclear receptors in breast cancer, with a particular focus on two of the estrogen-related receptors (ERRα and ERRγ) and several others implicated in clinical outcome and response or resistance to cytotoxic or endocrine therapies, including the chicken ovalbumin upstream promoter transcription factors, nerve growth factor-induced B, DAX-1, liver receptor homolog-1, and retinoic acid-related orphan receptor α. We also propose that a clearer understanding of the function of orphan nuclear receptors in mammary gland development and normal mammary tissues could significantly improve our ability to diagnose, treat, and prevent breast cancer.

Orphan Nuclear Receptors in Reproduction: Lessons from Tissue-Specific Knockout Mice.

2011 ◽  
Vol 85 (Suppl_1) ◽  
pp. 161-161
Author(s):  
Cong Zhang ◽  
Kalyne Bertolin ◽  
Raj Duggavathi ◽  
Bruce D. Murphy
Keyword(s):  
Nuclear Receptors ◽  
Knockout Mice ◽  
Orphan Nuclear Receptors ◽  
Tissue Specific

Orphan nuclear receptors: therapeutic opportunities in skeletal muscle

2006 ◽  
Vol 291 (2) ◽  
pp. C203-C217 ◽  
Author(s):  
Aaron G. Smith ◽  
George E. O. Muscat
Keyword(s):  
Cardiovascular Disease ◽  
Skeletal Muscle ◽  
Energy Expenditure ◽  
Nuclear Receptors ◽  
Hormone Receptors ◽  
Blood Lipid ◽  
Orphan Nuclear Receptors ◽  
Blood Lipid Profile ◽  
Total Body Mass ◽  
Liver And Kidney

Nuclear hormone receptors (NRs) are ligand-dependent transcription factors that bind DNA and translate physiological signals into gene regulation. The therapeutic utility of NRs is underscored by the diversity of drugs created to manage dysfunctional hormone signaling in the context of reproductive biology, inflammation, dermatology, cancer, and metabolic disease. For example, drugs that target nuclear receptors generate over $10 billion in annual sales. Almost two decades ago, gene products were identified that belonged to the NR superfamily on the basis of DNA and protein sequence identity. However, the endogenous and synthetic small molecules that modulate their action were not known, and they were denoted orphan NRs. Many of the remaining orphan NRs are highly enriched in energy-demanding major mass tissues, including skeletal muscle, brown and white adipose, brain, liver, and kidney. This review focuses on recently adopted and orphan NR function in skeletal muscle, a tissue that accounts for ∼35% of the total body mass and energy expenditure, and is a major site of fatty acid and glucose utilization. Moreover, this lean tissue is involved in cholesterol efflux and secretes that control energy expenditure and adiposity. Consequently, muscle has a significant role in insulin sensitivity, the blood lipid profile, and energy balance. Accordingly, skeletal muscle plays a considerable role in the progression of dyslipidemia, diabetes, and obesity. These are risk factors for cardiovascular disease, which is the the foremost cause of global mortality (>16.7 million deaths in 2003). Therefore, it is not surprising that orphan NRs and skeletal muscle are emerging as therapeutic candidates in the battle against dyslipidemia, diabetes, obesity, and cardiovascular disease.

scholarly journals Familial Focal Segmental Glomerulosclerosis (FSGS)-linked α-Actinin 4 (ACTN4) Protein Mutants Lose Ability to Activate Transcription by Nuclear Hormone Receptors

2012 ◽  
Vol 287 (15) ◽  
pp. 12027-12035 ◽  
Author(s):  
Simran Khurana ◽  
Sharmistha Chakraborty ◽  
Minh Lam ◽  
Yu Liu ◽  
Yu-Ting Su ◽  
...  
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Transcriptional Activity ◽  
Hormone Receptors ◽  
Retinoic Acid Receptor ◽  
Nuclear Hormone Receptors ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Segmental Glomerulosclerosis

Mutations in α-actinin 4 (ACTN4) are linked to familial forms of focal segmental glomerulosclerosis (FSGS), a kidney disease characterized by proteinuria due to podocyte injury. The mechanisms underlying ACTN4 mutant-associated FSGS are not completely understood. Although α-actinins are better known to cross-link actin filaments and modulate cytoskeletal organization, we have previously shown that ACTN4 interacts with transcription factors including estrogen receptor and MEF2s and potentiates their transcriptional activity. Nuclear receptors including retinoic acid receptor (RAR) have been proposed to play a protective role in podocytes. We show here that ACTN4 interacts with and enhances transcriptional activation by RARα. In addition, FSGS-linked ACTN4 mutants not only mislocalized to the cytoplasm, but also lost their ability to associate with nuclear receptors. Consequently, FSGS-linked ACTN4 mutants failed to potentiate transcriptional activation by nuclear hormone receptors in podocytes. In addition, overexpression of these mutants suppressed the transcriptional activity mediated by endogenous wild-type ACTN4 possibly by a cytoplasmic sequestration mechanism. Our data provide the first link between FSGS-linked ACTN4 mutants and transcriptional activation by nuclear receptor such as RARα and peroxisome proliferator-activated receptor γ.

scholarly journals Human ERRγ, a Third Member of the Estrogen Receptor-Related Receptor (ERR) Subfamily of Orphan Nuclear Receptors: Tissue-Specific Isoforms Are Expressed during Development and in the Adult

2000 ◽  
Vol 14 (3) ◽  
pp. 382-392 ◽  
Author(s):  
David J. Heard ◽  
Peder L. Norby ◽  
Jim Holloway ◽  
Henrik Vissing
Keyword(s):  
Estrogen Receptor ◽  
Nuclear Receptors ◽  
Expression Patterns ◽  
Protein Isoforms ◽  
Hek293 Cells ◽  
Receptor Protein ◽  
Orphan Nuclear Receptors ◽  
Independent Manner ◽  
Tissue Specific ◽  
Alternatively Spliced

Abstract The nuclear receptor protein superfamily is a large group of transcription factors involved in many aspects of animal development, tissue differentiation, and homeostasis in the higher eukaryotes. A subfamily of receptors, ERRα and β (estrogen receptor-related receptor α and β), closely related to the ER, were among the first orphan nuclear receptors identified. These receptors can bind DNA as monomers and are thought to activate transcription constitutively, unaffected by β-estradiol. Studies of the expression patterns of ERRα and gene disruption experiments of ERRβ indicate that they play an important role in the development and differentiation of specific tissues in the mouse. In this work we demonstrate the existence in humans of a third member of this subfamily of receptors, termed ERRγ, which is highly expressed in a number of diverse fetal and adult tissues including brain, kidney, pancreas, and placenta. The ERRγ mRNA is highly alternatively spliced at the 5′-end, giving rise to a number of tissue-specific RNA species, some of which code for protein isoforms differing in the N-terminal region. Like ERRα andβ , ERRγ binds as a monomer to an ERRE. A GAL4-ERRγ fusion protein activates transcription in a ligand-independent manner in transfected HEK293 cells to a greater degree than either the GAL4-ERRα or -β fusion proteins.

Ginseng on Nuclear Hormone Receptors

2017 ◽  
Vol 45 (06) ◽  
pp. 1147-1156 ◽  
Author(s):  
Joonwoo Park ◽  
Phuong T. C. Bui ◽  
Heewon Song ◽  
Si-Kwan Kim ◽  
Dong-Kwon Rhee ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Hormone Receptors ◽  
Specific Binding ◽  
First Record ◽  
Scientific Basis ◽  
Nuclear Hormone Receptors ◽  
Peroxisome Proliferator ◽  
Cellular Targets ◽  
Beneficial Effects ◽  
Bioactive Ingredients

The first record of ginseng use dates back over two millennia, and ginseng is now popular in more than 35 countries. Ginsenosides are the pharmacological constituents responsible for the beneficial effects of ginseng. There is increasing evidence that ginseng and its bioactive ingredients are involved in the regulation of nuclear receptors, molecules that act in response to the specific binding of hormones, which link to a diverse array of signaling pathways, such as the ERK and PI3K/Akt pathways. Knowledge of the mechanism of how ginseng mediates these complexes is essential for the development of multi-target phytomedicine as possible therapy for different diseases. Here, we discuss the literature on the effects of ginseng and its constituents on estrogen, glucocorticoid, peroxisome proliferator-activated, and androgen nuclear hormone receptors, as well as how ginseng and its constituents exert their biological function in the treatment of cancer, obesity, and cardiovascular and neurological disorders. The accumulated results definitely show that the nuclear receptors are cellular targets of ginsenosides, but more rigorous data are required to establish and provide a scientific basis to confirm the suggested efficacy of ginseng or products with ginsenosides.

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