Human ERR , 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

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.

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

Cells ◽

10.3390/cells8111373 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1373 ◽

Cited By ~ 11

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.

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Expression of estrogen receptor-related receptors, a subfamily of orphan nuclear receptors, as new tumor biomarkers in ovarian cancer cells

Journal of Molecular Medicine ◽

10.1007/s00109-005-0639-3 ◽

2005 ◽

Vol 83 (6) ◽

pp. 457-467 ◽

Cited By ~ 65

Author(s):

Pengming Sun ◽

Jalid Sehouli ◽

Carsten Denkert ◽

Alexander Mustea ◽

Dominique Könsgen ◽

...

Keyword(s):

Ovarian Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Nuclear Receptors ◽

Ovarian Cancer Cells ◽

Tumor Biomarkers ◽

Orphan Nuclear Receptors

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

Biology of Reproduction ◽

10.1093/biolreprod/85.s1.161 ◽

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

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Interplay between liganded and orphan nuclear receptors controls reproductive pathways

Biochemistry and Cell Biology ◽

10.1139/o00-057 ◽

2000 ◽

Vol 78 (3) ◽

pp. 345-358 ◽

Cited By ~ 6

Author(s):

Raphaël Métivier ◽

Yves Le Dréan ◽

Gilles Salbert ◽

Farzad Pakdel

Keyword(s):

Estrogen Receptor ◽

Transcriptional Regulation ◽

Transcription Factors ◽

Cell Fate ◽

Nuclear Receptors ◽

Gene Transcription ◽

Transcription Rate ◽

Orphan Nuclear Receptors ◽

Estrogen Binding ◽

Small Hydrophobic

Nuclear receptors are transcription factors that belong to an evolutionary ancient superfamily. These proteins, which are even present in primitive metazoans, are implicated in all levels of cell fate: proliferation, differentiation, and apoptosis. Some of these nuclear receptors behave as ligand-inducible transcription factors, as they have acquired during evolution the ability to bind ligands. This is the case for some proteins that recognize small hydrophobic signaling molecules, and particularly the estrogen receptor (ER or NR3A1), which regulates the target gene's transcription rate under estrogen binding. It is now known that the ER alone regulates the transcription of many genes, such as those implicated in reproductive functions. However, this ER-mediated signaling pathway could be modulated by other transcription factors. Our work has established that two other orphan nuclear receptors (SF-1 or NR5A1 and the COUP-TFs, NR2F1 and NR2F2) can enhance two ER-regulated genes implicated in salmonid reproductive functions: the ER gene itself, and the sGTHIIβ gene. Moreover, some xenoestrogens could disturb these regulations. Therefore, our data contribute to the concept that interplay between nuclear receptors is an important event for the transcriptional regulation of genes controlling cellular functions.Key words: reproduction, estrogen receptor, SF-1, COUP-TFI, gene transcription, xenobiotics.

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Tissue-specific expression patterns of nuclear receptors

NURSA Datasets ◽

10.1621/datasets.02001 ◽

2013 ◽

Author(s):

AL Bookout ◽

Y Jeong ◽

M Downes ◽

RT Yu ◽

RM Evans ◽

...

Keyword(s):

Nuclear Receptors ◽

Expression Patterns ◽

Specific Expression ◽

Tissue Specific ◽

Tissue Specific Expression

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Faculty Opinions recommendation of T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1100204.555260 ◽

2008 ◽

Author(s):

Lars Rogge

Keyword(s):

Nuclear Receptors ◽

T Helper ◽

Orphan Nuclear Receptors ◽

T Helper 17 ◽

Lineage Differentiation

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Local Regulation of Adrenal Steroidogenesis: Subtle in vitro Effects of IL-1β on the Human Cell Line NCI-H295R Steroid Production along with Changes in MicroRNA Profile and Orphan Nuclear Receptors NR4As

NeuroImmunoModulation ◽

10.1159/000512325 ◽

2021 ◽

pp. 1-11

Author(s):

Natalia Santucci ◽

Rocío Stampone ◽

Eduardo Brandão Ferreira da Silva ◽

Silvina Villar ◽

Silvana Spinelli ◽

...

Keyword(s):

Adrenal Gland ◽

Cell Line ◽

Nuclear Receptors ◽

Human Cell ◽

Human Cell Line ◽

Mirna Profile ◽

Orphan Nuclear Receptors ◽

Steroid Production ◽

Adrenal Steroid ◽

Adrenal Steroidogenesis

Introduction: IL-1β, a cytokine from the innate immune response, is well known for its proinflammatory effects and stimulating activity on the hypothalamus-pituitary-adrenal axis, leading to the pituitary synthesis of adrenocorticotropic hormone followed by cortisol (and dehydroepiandrosterone – DHEA) release by the adrenal gland. While IL-1β modulates the adrenal steroidogenesis at the central level, it is unclear whether it also exerts an effect on the adrenal gland. Method: We studied the effect of IL-1β on adrenal steroid production and steroidogenic enzyme RNA expression in the human cell line NCI-H295R. We also explored eventual changes in the microRNA (miRNA) profile from IL-1β-treated NCI-H295R cells. Results: Transcripts encoding IL-1β receptors 1 and 2 were noticeable in the cell line, with cortisol and DHEA production showing a subtle increase after cytokine treatment. Transcripts from key enzymes in the steroidogenic pathway were analyzed, with no noticeable changes on them. The miRNA profile was modified by IL-1β treatment to an extent which bears some relationship with the regulatory mechanisms underlying adrenal steroid production. Since orphan nuclear receptors NR4As have emerged as potential key factors for coordinating inflammatory and metabolic responses, cell expression studies were also carried out to show an NR4As transcript augmentation following IL-1β treatment. Discussion/Conclusions: The subtle increase in adrenal steroid production in response to IL-1β stimulation without any modification in the transcription of the steroidogenic enzymes analyzed suggests an additional inflammatory/anti-inflammatory loop, wherein NR4As receptors may participate. Besides its physiological role, this process might be implied in pathological states accompanied by an unbalanced immune-endocrine relationship.

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