The evolution of the nuclear receptor superfamily

2004 ◽  
Vol 40 ◽  
pp. 11-26 ◽  
Author(s):  
Héctor Escriva ◽  
Stéphanie Bertrand ◽  
Vincent Laudet
Keyword(s):  
Transcription Factors ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Evolutionary History ◽  
Hormone Receptors ◽  
Nuclear Receptor Superfamily ◽  
Complete Genomes ◽  
High Degree ◽  
Animal Genomes

Nuclear receptors form a superfamily of ligand-activated transcription factors implicated in various physiological functions from development to homoeostasis. Nuclear receptors share a common evolutionary history revealed by their conserved structure and by their high degree of sequence conservation. Here we review the latest advances on the evolution of nuclear receptors by addressing the following questions. What is known about the appearance and diversification of nuclear hormone receptors? How did their different functional characteristics evolve? What can we infer from the analysis of complete genomes? In summary, the study of the evolution of nuclear receptors will be very important not only for understanding their functions in vivo but also for obtaining insights into the evolution of animal genomes as a whole.

scholarly journals Structure and Function of the Nuclear Receptor Superfamily and Current Targeted Therapies of Prostate Cancer

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1852 ◽  
Author(s):  
Baylee A. Porter ◽  
Maria A. Ortiz ◽  
Gennady Bratslavsky ◽  
Leszek Kotula
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Nuclear Receptor ◽  
Hormone Receptors ◽  
Cell Permeability ◽  
Cancer Therapies ◽  
Functional Difference ◽  
Nuclear Receptor Superfamily ◽  
Functional Regulation ◽  
And Function

The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival, and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, we utilize the initial classification system, which defines subfamilies based on structure and functional difference. The defining feature of the nuclear receptor superfamily is that these proteins function as transcription factors. The loss of transcriptional regulation or gain of functioning of these receptors is a hallmark in numerous diseases. For example, in prostate cancer, the androgen receptor is a primary target for current prostate cancer therapies. Targeted cancer therapies for nuclear hormone receptors have been more feasible to develop than others due to the ligand availability and cell permeability of hormones. To better target these receptors, it is critical to understand their structural and functional regulation. Given that late-stage cancers often develop hormone insensitivity, we will explore the strengths and pitfalls of targeting other transcription factors outside of the nuclear receptor superfamily such as the signal transducer and activator of transcription (STAT).

scholarly journals Structure and Function of the Nuclear Receptor Superfamily and Current Targeted Therapies of Prostate Cancer

2019 ◽  
Author(s):  
Baylee Porter ◽  
Maria A. Ortiz ◽  
Gennady Bratslavsky ◽  
Leszek Kotula
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Nuclear Receptor ◽  
Hormone Receptors ◽  
Cell Permeability ◽  
Cancer Therapies ◽  
Functional Difference ◽  
Nuclear Receptor Superfamily ◽  
Functional Regulation ◽  
And Function

The nuclear receptor superfamily comprises a large group of proteins with functions essential for cell signaling, survival and proliferation. There are multiple distinctions between nuclear superfamily classes defined by hallmark differences in function, ligand binding, tissue specificity, and DNA binding. In this review, we utilize the initial classification system, which defines subfamilies based on structure and functional difference. The defining feature of the nuclear receptor superfamily is that these proteins function as transcription factors. The loss of transcriptional regulation or gain of functioning of these receptors is a hallmark in numerous diseases. For example, in prostate cancer the androgen receptor is a primary target for current prostate cancer therapies. Targeted cancer therapies for nuclear hormone receptors have been more feasible than others to develop due to ligand availability and cell permeability of hormones. To better target these receptors, it is critical to understand their structural and functional regulation. Given that late-stage cancers often develop hormone insensitivity, we will explore the strengths and pitfalls of targeting other transcription factors outside of the nuclear receptor superfamily such as the signal transducer and activator of transcription (STAT).

scholarly journals Sex Hormone Receptor Signals in Human Malignancies

2019 ◽  
Vol 20 (11) ◽  
pp. 2677
Author(s):  
Hiroshi Miyamoto
Keyword(s):  
Transcription Factors ◽  
Nuclear Receptor ◽  
Reproductive System ◽  
Sex Steroids ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Sex Hormone ◽  
Nuclear Receptor Superfamily ◽  
Sex Hormone Receptor

Sex steroids, including androgens, estrogens, and progestogens, are known to have widespread physiological actions beyond the reproductive system via binding to the sex hormone receptors, members of the nuclear receptor superfamily that function as ligand-inducible transcription factors [...]

scholarly journals Activating Signal Cointegrator 2 Belongs to a Novel Steady-State Complex That Contains a Subset of Trithorax Group Proteins

2003 ◽  
Vol 23 (1) ◽  
pp. 140-149 ◽  
Author(s):  
Young-Hwa Goo ◽  
Young Chang Sohn ◽  
Dae-Hwan Kim ◽  
Seung-Whan Kim ◽  
Min-Jung Kang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Steady State ◽  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Retinoic Acid Receptor ◽  
Dependent Manner ◽  
Trithorax Group ◽  
Trithorax Group Proteins

ABSTRACT Many transcription coactivators interact with nuclear receptors in a ligand- and C-terminal transactivation function (AF2)-dependent manner. These include activating signal cointegrator 2 (ASC-2), a recently isolated transcriptional coactivator molecule, which is amplified in human cancers and stimulates transactivation by nuclear receptors and numerous other transcription factors. In this report, we show that ASC-2 belongs to a steady-state complex of approximately 2 MDa (ASC-2 complex [ASCOM]) in HeLa nuclei. ASCOM contains retinoblastoma-binding protein RBQ-3, α/β-tubulins, and trithorax group proteins ALR-1, ALR-2, HALR, and ASH2. In particular, ALR-1/2 and HALR contain a highly conserved 130- to 140-amino-acid motif termed the SET domain, which was recently implicated in histone H3 lysine-specific methylation activities. Indeed, recombinant ALR-1, HALR, and immunopurified ASCOM exhibit very weak but specific H3-lysine 4 methylation activities in vitro, and transactivation by retinoic acid receptor appears to involve ligand-dependent recruitment of ASCOM and subsequent transient H3-lysine 4 methylation of the promoter region in vivo. Thus, ASCOM may represent a distinct coactivator complex of nuclear receptors. Further characterization of ASCOM will lead to a better understanding of how nuclear receptors and other transcription factors mediate transcriptional activation.

scholarly journals Minireview: Nuclear Receptor-Controlled Steroid Hormone Synthesis and Metabolism

2010 ◽  
Vol 24 (1) ◽  
pp. 11-21 ◽  
Author(s):  
Jinhan He ◽  
Qiuqiong Cheng ◽  
Wen Xie
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Steroid Hormones ◽  
Nuclear Receptor ◽  
Recent Progress ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Etiological Factor ◽  
Hormone Synthesis

Abstract Steroid hormones are essential in normal physiology whereas disruptions in hormonal homeostasis represent an important etiological factor for many human diseases. Steroid hormones exert most of their functions through the binding and activation of nuclear hormone receptors (NRs or NHRs), a superfamily of DNA-binding and often ligand-dependent transcription factors. In recent years, accumulating evidence has suggested that NRs can also regulate the biosynthesis and metabolism of steroid hormones. This review will focus on the recent progress in our understanding of the regulatory role of NRs in hormonal homeostasis and the implications of this regulation in physiology and diseases.

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 DRIP Complex and SRC-1/p160 Coactivators Share Similar Nuclear Receptor Binding Determinants but Constitute Functionally Distinct Complexes

2000 ◽  
Vol 20 (8) ◽  
pp. 2718-2726 ◽  
Author(s):  
Christophe Rachez ◽  
Matthew Gamble ◽  
Chao-Pei Betty Chang ◽  
G. Brandon Atkins ◽  
Mitchell A. Lazar ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Receptor Binding ◽  
Transcriptional Activation ◽  
Thyroid Hormone Receptor ◽  
Nuclear Receptor Coactivators ◽  
Nuclear Extracts ◽  
Sequence Requirements

ABSTRACT Transcriptional activation requires both access to DNA assembled as chromatin and functional contact with components of the basal transcription machinery. Using the hormone-bound vitamin D3receptor (VDR) ligand binding domain (LBD) as an affinity matrix, we previously identified a novel multisubunit coactivator complex, DRIP (VDR-interacting proteins), required for transcriptional activation by nuclear receptors and several other transcription factors. In this report, we characterize the nuclear receptor binding features of DRIP205, a key subunit of the DRIP complex, that interacts directly with VDR and thyroid hormone receptor in response to ligand and anchors the other DRIP subunits to the nuclear receptor LBD. In common with other nuclear receptor coactivators, DRIP205 interaction occurs through one of two LXXLL motifs and requires the receptor's AF-2 subdomain. Although the second motif of DRIP205 is required only for VDR binding in vitro, both motifs are used in the context of an retinoid X receptor-VDR heterodimer on DNA and in transactivation in vivo. We demonstrate that both endogenous p160 coactivators and DRIP complexes bind to the VDR LBD from nuclear extracts through similar sequence requirements, but they do so as distinct complexes. Moreover, in contrast to the p160 family of coactivators, the DRIP complex is devoid of any histone acetyltransferase activity. The results demonstrate that different coactivator complexes with distinct functions bind to the same transactivation region of nuclear receptors, suggesting that they are both required for transcription activation by nuclear receptors.

scholarly journals Reduced Fat Mass in Mice Lacking Orphan Nuclear Receptor Estrogen-Related Receptor α

2003 ◽  
Vol 23 (22) ◽  
pp. 7947-7956 ◽  
Author(s):  
Jiangming Luo ◽  
Robert Sladek ◽  
Julie Carrier ◽  
Jo-Ann Bader ◽  
Denis Richard ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Metabolic Regulation ◽  
Hormone Receptors ◽  
Target Genes ◽  
Serum Biochemistry ◽  
Orphan Nuclear Receptor ◽  
Steroid Synthesis ◽  
Fat Deposits ◽  
Estrogen Related Receptor

ABSTRACT The estrogen-related receptor α (ERRα) is an orphan member of the superfamily of nuclear hormone receptors expressed in tissues that preferentially metabolize fatty acids. Despite the molecular characterization of ERRα and identification of target genes, determination of its physiological function has been hampered by the lack of a natural ligand. To further understand the in vivo function of ERRα, we generated and analyzed Estrra-null (ERRα−/−) mutant mice. Here we show that ERRα−/− mice are viable, fertile and display no gross anatomical alterations, with the exception of reduced body weight and peripheral fat deposits. No significant changes in food consumption and energy expenditure or serum biochemistry parameters were observed in the mutant animals. However, the mutant animals are resistant to a high-fat diet-induced obesity. Importantly, DNA microarray analysis of gene expression in adipose tissue demonstrates altered regulation of several enzymes involved in lipid, eicosanoid, and steroid synthesis, suggesting that the loss of ERRα might interfere with other nuclear receptor signaling pathways. In addition, the microarray study shows alteration in the expression of genes regulating adipogenesis as well as energy metabolism. In agreement with these findings, metabolic studies showed reduced lipogenesis in adipose tissues. This study suggests that ERRα functions as a metabolic regulator and that the ERRα−/− mice provide a novel model for the investigation of metabolic regulation by nuclear receptors.

scholarly journals Hormone receptor 4 is required in muscles and distinct ovarian cell types to regulate specific steps of Drosophila oogenesis

Development ◽  
2021 ◽  
pp. dev.198663
Author(s):  
Lesley N. Weaver ◽  
Daniela Drummond-Barbosa
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Hormone Receptor ◽  
Cell Types ◽  
Germline Stem Cell ◽  
Follicle Growth ◽  
Peripheral Tissues ◽  
Ovarian Cell ◽  
Nuclear Receptor Superfamily ◽  
Germline Cyst

The conserved nuclear receptor superfamily has critical roles in many processes, including reproduction. Nuclear receptors with known roles in oogenesis have been studied mostly in the context of their ovary-intrinsic requirement. Recent studies in Drosophila, however, have begun to reveal new roles of nuclear receptor signaling in peripheral tissues in controlling reproduction. Here, we identified Hormone receptor 4 (Hr4) as an oogenesis regulator required in the ovary and muscles. Global Hr4 knockdown leads to increased germline stem cell (GSC) loss, reduced GSC proliferation, early germline cyst death, slowed follicle growth, and vitellogenic follicle degeneration. Tissue-specific knockdown experiments uncovered ovary-intrinsic and peripheral tissue requirements for Hr4. In the ovary, Hr4 is required in the niche for GSC proliferation and in the germline for GSC maintenance. Hr4 functions in muscles to promote GSC maintenance and follicle growth. The specific tissues that require Hr4 for survival of early germline cysts and vitellogenic follicles remain unidentified. These results add to the few examples of muscles controlling gametogenesis and expand our understanding of the complexity of nuclear receptor regulation of various aspects of oogenesis.

scholarly journals BAF60a Mediates Critical Interactions between Nuclear Receptors and the BRG1 Chromatin-Remodeling Complex for Transactivation

2003 ◽  
Vol 23 (17) ◽  
pp. 6210-6220 ◽  
Author(s):  
Pei-Wen Hsiao ◽  
Christy J. Fryer ◽  
Kevin W. Trotter ◽  
Weidong Wang ◽  
Trevor K. Archer
Keyword(s):  
Nuclear Receptors ◽  
Chromatin Remodeling ◽  
Molecular Mechanisms ◽  
Hormone Receptors ◽  
Nuclear Receptor Coactivators ◽  
Chromatin Remodeling Complex ◽  
Truncation Mutant ◽  
Promoter Recruitment

ABSTRACT Nuclear hormone receptors are ligand-dependent transcriptional regulators that modulate chromatin structure. However, the precise molecular mechanisms by which receptors recruit chromatin-remodeling activity are not fully elucidated. We show that in the absence of its ligand-binding domain, the glucocorticoid receptor (GR) is able to interact with both nuclear receptor coactivators and the BRG1 chromatin-remodeling complex in vivo. Individually, the GR makes direct interactions with BRG1-associated factor 60a (BAF60a) and BAF57, but not with BRG1, BAF155, or BAF170. Further, BAF60a possesses at least two interaction surfaces, one for GR and BRG1 and a second for BAF155 and BAF170. A GR mutant, GR(R488Q), that fails to interact with BAF60a in vitro has reduced chromatin-remodeling activity and reduced transcriptional activity from the promoter assembled as chromatin in vivo. Stable expression of a BAF60a truncation mutant, BAF60a4-140, caused chromatin-specific loss of GR functions in vivo. In the presence of the BAF60a mutant, the GR fails to interact with the BRG1 complex and consequently is also deficient in its ability to activate transcription from chromatin. Thus, in addition to previously identified BAF250, BAF60a may provide another critical and direct link between nuclear receptors and the BRG1 complex that is required for promoter recruitment and subsequent chromatin remodeling.

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