Special Issue "Functions of Nuclear Receptors"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (31 August 2019).

Special Issue Editor

Dr. Hiroshi Miyamoto
E-Mail Website
Guest Editor
Director of Genitourinary Pathology, University of Rochester Medical Center, Rochester, NY, USA
Interests: nuclear hormone receptors; androgen receptor; glucocorticoid receptor; antiandrogens; glucocorticoids; urothelial cancer; prostate cancer; genitourinary pathology
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Nuclear receptors are a class of proteins classified as transcription factors that regulate the expression of specific genes, including those involving critical biological functions such as development, homeostasis, and metabolism, via binding of their cognate ligands. Nearly 50 nuclear receptor family members encoded in the human/mouse/rat genome have been identified. Recently, a large body of evidence has emerged suggesting that nuclear receptors play an important role in pathological conditions such as the development and progression of neoplasms. However, exact functions of nuclear receptors remain far from being fully understood. The aim of this Special Issue is to provide an overview of previous and novel findings indicating the functional role of nuclear receptors in physiological conditions as well as a variety of disorders. Original research or review articles on signaling related to any nuclear receptors are most welcome.

Dr. Hiroshi Miyamoto
Guest Editor

Manuscript Submission Information

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Keywords

  • Nuclear receptors
  • Steroid hormone receptors
  • Retinoid receptors
  • Orphan receptors
  • Transactivation
  • Transrepression
  • Non-genomic effects
  • Coactivators
  • Corepressors
  • Agonists
  • Antagonists

Published Papers (11 papers)

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Research

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Open AccessArticle
Hits Discovery on the Androgen Receptor: In Silico Approaches to Identify Agonist Compounds
Cells 2019, 8(11), 1431; https://doi.org/10.3390/cells8111431 - 13 Nov 2019
Abstract
The androgen receptor (AR) is a transcription factor that plays a key role in sexual phenotype and neuromuscular development. AR can be modulated by exogenous compounds such as pharmaceuticals or chemicals present in the environment, and particularly by AR agonist compounds that mimic [...] Read more.
The androgen receptor (AR) is a transcription factor that plays a key role in sexual phenotype and neuromuscular development. AR can be modulated by exogenous compounds such as pharmaceuticals or chemicals present in the environment, and particularly by AR agonist compounds that mimic the action of endogenous agonist ligands and whether restore or alter the AR endocrine system functions. The activation of AR must be correctly balanced and identifying potent AR agonist compounds is of high interest to both propose treatments for certain diseases, or to predict the risk related to agonist chemicals exposure. The development of in silico approaches and the publication of structural, affinity and activity data provide a good framework to develop rational AR hits prediction models. Herein, we present a docking and a pharmacophore modeling strategy to help identifying AR agonist compounds. All models were trained on the NR-DBIND that provides high quality binding data on AR and tested on AR-agonist activity assays from the Tox21 initiative. Both methods display high performance on the NR-DBIND set and could serve as starting point for biologists and toxicologists. Yet, the pharmacophore models still need data feeding to be used as large scope undesired effect prediction models. Full article
(This article belongs to the Special Issue Functions of Nuclear Receptors)
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Open AccessArticle
Regulation of RXR-RAR Heterodimers by RXR- and RAR-Specific Ligands and Their Combinations
Cells 2019, 8(11), 1392; https://doi.org/10.3390/cells8111392 - 05 Nov 2019
Abstract
The three subtypes (α, β, and γ) of the retinoic acid receptor (RAR) are ligand-dependent transcription factors that mediate retinoic acid signaling by forming heterodimers with the retinoid X receptor (RXR). Heterodimers are functional units that bind ligands (retinoids), transcriptional co-regulators and DNA, [...] Read more.
The three subtypes (α, β, and γ) of the retinoic acid receptor (RAR) are ligand-dependent transcription factors that mediate retinoic acid signaling by forming heterodimers with the retinoid X receptor (RXR). Heterodimers are functional units that bind ligands (retinoids), transcriptional co-regulators and DNA, to regulate gene networks controlling cell growth, differentiation, and death. Using biochemical, crystallographic, and cellular approaches, we have set out to explore the spectrum of possibilities to regulate RXR-RAR heterodimer-dependent transcription through various pharmacological classes of RAR- and RXR- specific ligands, alone or in combination. We reveal the molecular details by which these compounds direct specificity and functionality of RXR-RAR heterodimers. Among these ligands, we have reevaluated and improved the molecular and structural definition of compounds CD2665, Ro41-5253, LE135, or LG100754, highlighting novel functional features of these molecules. Our analysis reveals a model of RXR-RAR heterodimer action in which each subunit retains its intrinsic properties in terms of ligand and co-regulator binding. However, their interplay upon the combined action of RAR- and RXR-ligands allows for the fine tuning of heterodimer activity. It also stresses the importance of accurate ligand characterization to use synthetic selective retinoids appropriately and avoid data misinterpretations. Full article
(This article belongs to the Special Issue Functions of Nuclear Receptors)
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Open AccessArticle
Feeding Entrainment of the Zebrafish Circadian Clock Is Regulated by the Glucocorticoid Receptor
Cells 2019, 8(11), 1342; https://doi.org/10.3390/cells8111342 - 29 Oct 2019
Abstract
Glucocorticoids (GCs) are steroid hormones mainly acting as key regulators of body homeostasis and stress responses. Their activities are primarily based on the binding to the GC receptor (GR), a member of the nuclear receptor family, that regulates tissue-specific sets of genes. GCs [...] Read more.
Glucocorticoids (GCs) are steroid hormones mainly acting as key regulators of body homeostasis and stress responses. Their activities are primarily based on the binding to the GC receptor (GR), a member of the nuclear receptor family, that regulates tissue-specific sets of genes. GCs secretion follows a circadian rhythmicity with a peak linked to the animal’s activity phase. In mammals, GCs are also implicated in feeding entrainment mechanisms as internal zeitgeber. Here, we investigated, by means of behavioural and molecular approaches, the circadian clock and its regulation by light and food in wild-type (WT) and null glucocorticoid receptor (gr−/−) zebrafish larvae, juveniles and adults. In both WT and gr−/− larvae and adults, behavioural activity and clock gene expression were entrained to the light–dark (LD) cycle and rhythmic in constant conditions. Differences in the pattern of clock genes’ expression indicated a modulatory role of GCs. A significant role of Gr was detected in the feeding entrainment which was absent or markedly dampened in mutants. Furthermore, the expression of two clock-regulated genes involved in glucidic and lipidic metabolism was altered, highlighting the participation of GCs in metabolic processes also in fish. Taken together, our results confirmed the role of GC-mediated Gr signaling in the feeding entrainment in a non-mammalian species, the zebrafish. Full article
(This article belongs to the Special Issue Functions of Nuclear Receptors)
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Open AccessArticle
Transcriptomic Response to 1,25-Dihydroxyvitamin D in Human Fibroblasts with or without a Functional Vitamin D Receptor (VDR): Novel Target Genes and Insights into VDR Basal Transcriptional Activity
Cells 2019, 8(4), 318; https://doi.org/10.3390/cells8040318 - 05 Apr 2019
Abstract
The vitamin D receptor (VDR) mediates vitamin D actions beyond bone health. While VDR activation by 1,25-dihydroxyvitamin D (1,25D) leads to robust transcriptional regulation, less is known about VDR actions in the absence of 1,25D. We analyzed the transcriptomic response to 1,25D in [...] Read more.
The vitamin D receptor (VDR) mediates vitamin D actions beyond bone health. While VDR activation by 1,25-dihydroxyvitamin D (1,25D) leads to robust transcriptional regulation, less is known about VDR actions in the absence of 1,25D. We analyzed the transcriptomic response to 1,25D in fibroblasts bearing a severe homozygous hereditary vitamin D resistant rickets-related p.Arg30* VDR mutation (MUT) and in control fibroblasts (CO). Roughly 4.5% of the transcriptome was regulated by 1,25D in CO fibroblasts, while MUT cells without a functional VDR were insensitive to 1,25D. Novel VDR target genes identified in human fibroblasts included bone and cartilage factors CILP, EFNB2, and GALNT12. Vehicle-treated CO and MUT fibroblasts had strikingly different transcriptomes, suggesting basal VDR activity. Indeed, oppositional transcriptional effects in basal conditions versus after 1,25D activation were implied for a subset of target genes mostly involved with cell cycle. Cell proliferation assays corroborated this conjectured oppositional basal VDR activity, indicating that precise 1,25D dosage in target tissues might be essential for modulating vitamin D actions in human health. Full article
(This article belongs to the Special Issue Functions of Nuclear Receptors)
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Open AccessArticle
Involvement of Estrogen and Its Receptors in Morphological Changes in the Eyes of the Japanese Eel, Anguilla japonica, in the Process of Artificially-Induced Maturation
Cells 2019, 8(4), 310; https://doi.org/10.3390/cells8040310 - 03 Apr 2019
Cited by 2
Abstract
During the long migration from river habitats to the spawning ground, the Japanese eel undergoes sexual maturation. This spawning migration occurs concurrently with morphological changes, such as increases in eye size; however, the mechanisms by which sex steroids and their receptors influence these [...] Read more.
During the long migration from river habitats to the spawning ground, the Japanese eel undergoes sexual maturation. This spawning migration occurs concurrently with morphological changes, such as increases in eye size; however, the mechanisms by which sex steroids and their receptors influence these changes in peripheral tissues remain unclear. The aim of this study was to investigate changes in the eyes of female Japanese eels during sexual maturation, and our research focused on estrogen receptor (ER)α and ERβ transcripts. During ovarian development, the gonadosomatic index increased and yolk-laden oocytes developed rapidly. These changes occurred in conjunction with a steady increase in plasma levels of estradiol-17β (E2). Concomitant increases in transcript levels of ERα and ERβ in eye, brain, pituitary, and ovary were also observed. Fluorescence in-situ hybridization analyses revealed that ERα and ERβ transcripts were present in the choriocapillary layer and photoreceptor layer of the eyes, and the analysis also revealed that their signals in these layers became stronger in mature females compared to those observed in immature females, suggesting that under the influence of gonadotropins, morphological changes in the eyes are regulated by E2 through the activation of its receptors. In conclusion, E2 plays a crucial role in physiological adaptations that occur in peripheral tissues during the spawning migration. Full article
(This article belongs to the Special Issue Functions of Nuclear Receptors)
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Review

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Open AccessReview
Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues
Cells 2019, 8(11), 1373; https://doi.org/10.3390/cells8111373 - 01 Nov 2019
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Functions of Nuclear Receptors)
Open AccessFeature PaperReview
Androgens and Androgen Receptor Actions on Bone Health and Disease: From Androgen Deficiency to Androgen Therapy
Cells 2019, 8(11), 1318; https://doi.org/10.3390/cells8111318 - 25 Oct 2019
Abstract
Androgens are not only essential for bone development but for the maintenance of bone mass. Therefore, conditions with androgen deficiency, such as male hypogonadism, androgen-insensitive syndromes, and prostate cancer with androgen deprivation therapy are strongly associated with bone loss and increased fracture risk. [...] Read more.
Androgens are not only essential for bone development but for the maintenance of bone mass. Therefore, conditions with androgen deficiency, such as male hypogonadism, androgen-insensitive syndromes, and prostate cancer with androgen deprivation therapy are strongly associated with bone loss and increased fracture risk. Here we summarize the skeletal effects of androgens—androgen receptors (AR) actions based on in vitro and in vivo studies from animals and humans, and discuss bone loss due to androgens/AR deficiency to clarify the molecular basis for the anabolic action of androgens and AR in bone homeostasis and unravel the functions of androgen/AR signaling in healthy and disease states. Moreover, we provide evidence for the skeletal benefits of androgen therapy and elucidate why androgens are more beneficial than male sexual hormones, highlighting their therapeutic potential as osteoanabolic steroids in improving bone fracture repair. Finally, the application of selective androgen receptor modulators may provide new approaches for the treatment of osteoporosis and fractures as well as building stronger bones in diseases dependent on androgens/AR status. Full article
(This article belongs to the Special Issue Functions of Nuclear Receptors)
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Open AccessReview
The Glucocorticoid Receptor in Cardiovascular Health and Disease
Cells 2019, 8(10), 1227; https://doi.org/10.3390/cells8101227 - 09 Oct 2019
Cited by 2
Abstract
The glucocorticoid receptor is a member of the nuclear receptor family that controls many distinct gene networks, governing various aspects of development, metabolism, inflammation, and the stress response, as well as other key biological processes in the cardiovascular system. Recently, research in both [...] Read more.
The glucocorticoid receptor is a member of the nuclear receptor family that controls many distinct gene networks, governing various aspects of development, metabolism, inflammation, and the stress response, as well as other key biological processes in the cardiovascular system. Recently, research in both animal models and humans has begun to unravel the profound complexity of glucocorticoid signaling and convincingly demonstrates that the glucocorticoid receptor has direct effects on the heart and vessels in vivo and in vitro. This research has contributed directly to improving therapeutic strategies in human disease. The glucocorticoid receptor is activated either by the endogenous steroid hormone cortisol or by exogenous glucocorticoids and acts within the cardiovascular system via both genomic and non-genomic pathways. Polymorphisms of the glucocorticoid receptor are also reported to influence the progress and prognosis of cardiovascular disease. In this review, we provide an update on glucocorticoid signaling and highlight the critical role of this signaling in both physiological and pathological conditions of the cardiovascular system. With increasing in-depth understanding of glucocorticoid signaling, the future is promising for the development of targeted glucocorticoid treatments and improved clinical outcomes. Full article
(This article belongs to the Special Issue Functions of Nuclear Receptors)
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Open AccessReview
Importance of the Androgen Receptor Signaling in Gene Transactivation and Transrepression for Pubertal Maturation of the Testis
Cells 2019, 8(8), 861; https://doi.org/10.3390/cells8080861 - 09 Aug 2019
Abstract
Androgens are key for pubertal development of the mammalian testis, a phenomenon that is tightly linked to Sertoli cell maturation. In this review, we discuss how androgen signaling affects Sertoli cell function and morphology by concomitantly inhibiting some processes and promoting others that [...] Read more.
Androgens are key for pubertal development of the mammalian testis, a phenomenon that is tightly linked to Sertoli cell maturation. In this review, we discuss how androgen signaling affects Sertoli cell function and morphology by concomitantly inhibiting some processes and promoting others that contribute jointly to the completion of spermatogenesis. We focus on the molecular mechanisms that underlie anti-Müllerian hormone (AMH) inhibition by androgens at puberty, as well as on the role androgens have on Sertoli cell tight junction formation and maintenance and, consequently, on its effect on proper germ cell differentiation and meiotic onset during spermatogenesis. Full article
(This article belongs to the Special Issue Functions of Nuclear Receptors)
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Open AccessFeature PaperReview
The Role of Nuclear Receptors in Prostate Cancer
Cells 2019, 8(6), 602; https://doi.org/10.3390/cells8060602 - 17 Jun 2019
Abstract
The nuclear receptor (NR) superfamily consists of 48 members that are divided into seven subfamilies. NRs are transcription factors that play an important role in a number of biological processes. The NR superfamily includes androgen receptor, which is a key player in prostate [...] Read more.
The nuclear receptor (NR) superfamily consists of 48 members that are divided into seven subfamilies. NRs are transcription factors that play an important role in a number of biological processes. The NR superfamily includes androgen receptor, which is a key player in prostate cancer pathogenesis, suggesting the functional roles of other NRs in prostate cancer. The findings on the roles of NRs in prostate cancer thus far have shown that several NRs such as vitamin D receptor, estrogen receptor β, and mineralocorticoid receptor play antioncogenic roles, while other NRs such as peroxisome proliferator-activated receptor γ and estrogen receptor α as well as androgen receptor play oncogenic roles. However, the roles of other NRs in prostate cancer remain controversial or uninvestigated. Further research on the role of NRs in prostate cancer is required and may lead to the development of novel preventions and therapeutics for prostate cancer. Full article
(This article belongs to the Special Issue Functions of Nuclear Receptors)
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Open AccessFeature PaperReview
The Role of Androgen Receptor Signaling in Ovarian Cancer
Cells 2019, 8(2), 176; https://doi.org/10.3390/cells8020176 - 19 Feb 2019
Cited by 4
Abstract
Emerging evidence has suggested that androgen receptor signaling plays an important role in ovarian cancer outgrowth. Specifically, androgen receptor activation appears to be associated with increased risks of developing ovarian cancer and inducing tumor progression. However, conflicting findings have also been reported. This [...] Read more.
Emerging evidence has suggested that androgen receptor signaling plays an important role in ovarian cancer outgrowth. Specifically, androgen receptor activation appears to be associated with increased risks of developing ovarian cancer and inducing tumor progression. However, conflicting findings have also been reported. This review summarizes and discusses the available data indicating the involvement of androgens as well as androgen receptor and related signals in ovarian carcinogenesis and cancer growth. Although the underlying molecular mechanisms for androgen receptor functions in ovarian cancer remain far from being fully understood, current observations may offer effective chemopreventive and therapeutic approaches, via modulation of androgen receptor activity, against ovarian cancer. Indeed, several clinical trials have been conducted to determine the efficacy of androgen deprivation therapy in patients with ovarian cancer. Full article
(This article belongs to the Special Issue Functions of Nuclear Receptors)
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