Interplay between liganded and orphan nuclear receptors controls reproductive pathways

2000 ◽  
Vol 78 (3) ◽  
pp. 345-358 ◽  
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.

Super-Enhancer-Associated Transcription Factors Maintain Transcriptional Regulation in Mature Podocytes

2021 ◽  
pp. ASN.2020081177
Author(s):  
Jingping Yang ◽  
Difei Zhang ◽  
Masaru Motojima ◽  
Tsutomu Kume ◽  
Qing Hou ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Animal Models ◽  
Cell Fate ◽  
Control Cell ◽  
Transgenic Animal ◽  
Animal Models Of Disease ◽  
Super Enhancer ◽  
Models Of Disease ◽  
Human Glomerulus

BackgroundTranscriptional programs control cell fate, and identifying their components is critical for understanding diseases caused by cell lesion, such as podocytopathy. Although many transcription factors (TFs) are necessary for cell-state maintenance in glomeruli, their roles in transcriptional regulation are not well understood.MethodsThe distribution of H3K27ac histones in human glomerulus cells was analyzed to identify superenhancer-associated TFs, and ChIP-seq and transcriptomics were performed to elucidate the regulatory roles of the TFs. Transgenic animal models of disease were further investigated to confirm the roles of specific TFs in podocyte maintenance.ResultsSuperenhancer distribution revealed a group of potential TFs in core regulatory circuits in human glomerulus cells, including FOXC1/2, WT1, and LMX1B. Integration of transcriptome and cistrome data of FOXC1/2 in mice resolved transcriptional regulation in podocyte maintenance. FOXC1/2 regulated differentiation-associated transcription in mature podocytes. In both humans and animal models, mature podocyte injury was accompanied by deregulation of FOXC1/2 expression, and FOXC1/2 overexpression could protect podocytes in zebrafish.ConclusionsFOXC1/2 maintain podocyte differentiation through transcriptional stabilization. The genome-wide chromatin resources support further investigation of TFs’ regulatory roles in glomeruli transcription programs.

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 Graded repression of PU.1/Sfpi1 gene transcription by GATA factors regulates hematopoietic cell fate

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 983-994 ◽  
Author(s):  
Stella T. Chou ◽  
Eugene Khandros ◽  
L. Charles Bailey ◽  
Kim E. Nichols ◽  
Christopher R. Vakoc ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Gene Transcription ◽  
Target Genes ◽  
Hematopoietic Cell ◽  
Physical Interaction ◽  
Related Factor ◽  
Gata Factors ◽  
Undifferentiated State

GATA-1 and PU.1 are essential hematopoietic transcription factors that control erythromegakaryocytic and myelolymphoid differentiation, respectively. These proteins antagonize each other through direct physical interaction to repress alternate lineage programs. We used immortalized Gata1− erythromegakaryocytic progenitor cells to study how PU.1/Sfpi1 expression is regulated by GATA-1 and GATA-2, a related factor that is normally expressed at earlier stages of hematopoiesis. Both GATA factors bind the PU.1/Sfpi1 gene at 2 highly conserved regions. In the absence of GATA-1, GATA-2 binding is associated with an undifferentiated state, intermediate level PU.1/Sfpi1 expression, and low-level expression of its downstream myeloid target genes. Restoration of GATA-1 function induces erythromegakaryocytic differentiation. Concomitantly, GATA-1 replaces GATA-2 at the PU.1/Sfpi1 locus and PU.1/Sfpi1 expression is extinguished. In contrast, when GATA-1 is not present, shRNA knockdown of GATA-2 increases PU.1/Sfpi1 expression by 3-fold and reprograms the cells to become macrophages. Our findings indicate that GATA factors act sequentially to regulate lineage determination during hematopoiesis, in part by exerting variable repressive effects at the PU.1/Sfpi1 locus.

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.

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

2005 ◽  
Vol 83 (6) ◽  
pp. 457-467 ◽  
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

scholarly journals The interface of nuclear and membrane steroid signaling

Endocrinology ◽  
2021 ◽  
Author(s):  
Lindsey S Treviño ◽  
Daniel A Gorelick
Keyword(s):  
Estrogen Receptor ◽  
Transcription Factors ◽  
Membrane Proteins ◽  
Cell Membrane ◽  
Nuclear Receptors ◽  
Cell Nucleus ◽  
Androgen Receptors ◽  
Steroid Receptors ◽  
And Function

Abstract Steroid hormones bind receptors in the cell nucleus and in the cell membrane. The most widely studied class of steroid hormone receptors are the nuclear receptors, named for their function as ligand-dependent transcription factors in the cell nucleus. Nuclear receptors, such as estrogen receptor alpha, can also be anchored to the plasma membrane, where they respond to steroids by activating signaling pathways independent of their function as transcription factors. Steroids can also bind integral membrane proteins, such as the G protein-coupled estrogen receptor. Membrane estrogen and progestin receptors have been cloned and characterized in vitro and influence the development and function of many organ systems. Membrane androgen receptors were cloned and characterized in vitro, but their function as androgen receptors in vivo is unresolved. We review the identity and function of membrane proteins that bind estrogens, progestins and androgens. We discuss evidence that membrane glucocorticoid and mineralocorticoid receptors exist, and whether glucocorticoid and mineralocorticoid nuclear receptors act at the cell membrane. In many cases, integral membrane steroid receptors act independently of nuclear steroid receptors, even though they may share a ligand.

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.

scholarly journals Estrogen receptor and aryl hydrocarbon receptor signaling pathways

2006 ◽  
Vol 4 (1) ◽  
pp. nrs.04016 ◽  
Author(s):  
Jason Matthews ◽  
Jan-Åke Gustafsson
Keyword(s):  
Estrogen Receptor ◽  
Transcription Factors ◽  
Estrogen Receptors ◽  
Aryl Hydrocarbon Receptor ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Target Genes ◽  
Xenobiotic Metabolism ◽  
Positive Role ◽  
Aryl Hydrocarbon

Estrogen receptors (ERs) and the aryl hydrocarbon receptor (AhR) are ligand activated transcription factors and members of the nuclear receptor and bHLH-PAS superfamilies, respectively. AhR is involved in xenobiotic metabolism and in mediating the toxic effects of dioxin-like compounds. Crosstalk has been observed among AhR and nuclear receptors, but has been most well studied with respect to ER signaling. Activated AhR inhibits ER activity through a number of different mechanisms, whereas ERα has been reported to have a positive role in AhR signaling. Here we will discuss recent data revealing that dioxin bound AhR recruits ERα to AhR regulated genes. We will also consider the implications of ER recruitment to AhR target genes on ER and AhR signaling.

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