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 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 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.

Diversity and Function of Orphan Nuclear Receptors in Nematodes

2002 ◽  
Vol 12 (1) ◽  
pp. 24 ◽  
Author(s):  
Ann E. Sluder ◽  
Marc Van Gilst ◽  
Christopher R. Gissendanner
Keyword(s):  
Nuclear Receptors ◽  
Orphan Nuclear Receptors ◽  
And Function

Diversity and Function of Orphan Nuclear Receptors in Nematodes

2002 ◽  
Vol 12 (1) ◽  
pp. 24
Author(s):  
Christopher R. Gissendanner ◽  
Marc Van Gilst ◽  
Ann E. Sluder
Keyword(s):  
Nuclear Receptors ◽  
Orphan Nuclear Receptors ◽  
And Function

scholarly journals Role of Nuclear Receptors in Central Nervous System Development and Associated Diseases

2015 ◽  
Vol 9s2 ◽  
pp. JEN.S25480 ◽  
Author(s):  
Ana Ana Maria ◽  
Moreno-Ramos Oscar Andréas ◽  
Neena B. Haider
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Nuclear Receptors ◽  
System Development ◽  
Nuclear Hormone Receptor ◽  
Nervous System Development ◽  
Wide Range ◽  
And Function ◽  
The Impact

The nuclear hormone receptor (NHR) superfamily is composed of a wide range of receptors involved in a myriad of important biological processes, including development, growth, metabolism, and maintenance. Regulation of such wide variety of functions requires a complex system of gene regulation that includes interaction with transcription factors, chromatin-modifying complex, and the proper recognition of ligands. NHRs are able to coordinate the expression of genes in numerous pathways simultaneously. This review focuses on the role of nuclear receptors in the central nervous system and, in particular, their role in regulating the proper development and function of the brain and the eye. In addition, the review highlights the impact of mutations in NHRs on a spectrum of human diseases from autism to retinal degeneration.

scholarly journals Commentary: The Year in Orphan Nuclear Receptors and Their Coregulators

2011 ◽  
Vol 25 (12) ◽  
pp. 1983-1988
Author(s):  
David D. Moore
Keyword(s):  
Nuclear Receptors ◽  
Orphan Nuclear Receptors ◽  
Orphan Receptors ◽  
Wide Range ◽  
Basic Studies ◽  
Shed Light

Abstract We are beginning to integrate the functions of individual orphan receptors into larger networks. It is particularly exciting that these basic studies are beginning to shed light on important diseases. We are now able to address not just physiological but also pathological functions of these proteins and their potential as targets for treating a surprisingly wide range of diseases.

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 Nutrition–hormone receptor–gene interactions: implications for development and disease

2001 ◽  
Vol 60 (1) ◽  
pp. 63-72 ◽  
Author(s):  
M. J. Dauncey ◽  
P. White ◽  
K. A. Burton ◽  
M. Katsumata
Keyword(s):  
Nuclear Receptors ◽  
Gene Transcription ◽  
Hormone Receptors ◽  
Receptor Gene ◽  
Phenotypic Expression ◽  
Nutrient Utilization ◽  
Human Populations ◽  
Myosin Isoforms ◽  
Energy Status ◽  
Stage Of Development

Nutrition profoundly alters the phenotypic expression of a given genotype, particularly during fetal and postnatal development. Many hormones act as nutritional signals and their receptors play a key role in mediating the effects of nutrition on numerous genes involved in differentiation, growth and metabolism. Polypeptide hormones act on membrane-bound receptors to trigger gene transcription via complex intracellular signalling pathways. By contrast, nuclear receptors for lipid-soluble molecules such as glucocorticoids (GC) and thyroid hormones (TH) directly regulate transcription via DNA binding and chromatin remodelling. Nuclear hormone receptors are members of a large superfamily of transcriptional regulators with the ability to activate or repress many genes involved in development and disease. Nutrition influences not only hormone synthesis and metabolism but also hormone receptors, and regulation is mediated either by specific nutrients or by energy status. Recent studies on the role of early environment on development have implicated GC and their receptors in the programming of adult disease. Intrauterine growth restriction and postnatal undernutrition also induce striking differences in TH-receptor isoforms in functionally-distinct muscles, with critical implications for gene transcription of myosin isoforms, glucose transporters, uncoupling proteins and cation pumps. Such findings highlight a mechanism by which nutritional status can influence normal development, and modify nutrient utilization, thermogenesis, peripheral sensitivity to insulin and optimal cardiac function. Diet and stage of development will also influence the transcriptional activity of drugs acting as ligands for nuclear receptors. Potential interactions between nuclear receptors, including those for retinoic acid and vitamin D, should not be overlooked in intervention programmes using I or vitamin A supplementation of young and adult human populations.

Phasing the intranuclear organization of steroid hormone receptors

2021 ◽  
Vol 478 (2) ◽  
pp. 443-461
Author(s):  
Martin Stortz ◽  
Diego M. Presman ◽  
Adali Pecci ◽  
Valeria Levi
Keyword(s):  
Drug Targets ◽  
Hormone Receptors ◽  
Steroid Receptors ◽  
Current Knowledge ◽  
Steroid Hormone Receptors ◽  
New Paradigm ◽  
Theoretical Frameworks ◽  
New Ideas ◽  
And Function ◽  
Liquid Liquid Phase Separation

Steroid receptors (SRs) encompass a family of transcription factors that regulate the expression of thousands of genes upon binding to steroid hormones and include the glucocorticoid, androgen, progesterone, estrogen and mineralocorticoid receptors. SRs control key physiological and pathological processes, thus becoming relevant drug targets. As with many other nuclear proteins, hormone-activated SRs concentrate in multiple discrete foci within the cell nucleus. Even though these foci were first observed ∼25 years ago, their exact structure and function remained elusive. In the last years, new imaging methodologies and theoretical frameworks improved our understanding of the intranuclear organization. These studies led to a new paradigm stating that many membraneless nuclear compartments, including transcription-related foci, form through a liquid–liquid phase separation process. These exciting ideas impacted the SR field by raising the hypothesis of SR foci as liquid condensates involved in transcriptional regulation. In this work, we review the current knowledge about SR foci formation under the light of the condensate model, analyzing how these structures may impact SR function. These new ideas, combined with state-of-the-art techniques, may shed light on the biophysical mechanisms governing the formation of SR foci and the biological function of these structures in normal physiology and disease.

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