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Estrogen-related receptor ? (ERR?) - renaissance receptor or receptor renaissance?

ABSTRACT: Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERR? and ERR? at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERR?, however, has until recently been somewhat slower than that of its family members. ERR? has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERR? in mouse, man, and other species, highlighting unique aspects of ERR? biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor.

SUBMITTER: Divekar SD

PROVIDER: S-EPMC4978380 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Estrogen-related receptor β (ERRβ) - renaissance receptor or receptor renaissance?

Divekar Shailaja D SD Tiek Deanna M DM Fernandez Aileen A Riggins Rebecca B RB

Nuclear receptor signaling 20160621

Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRα and ERRγ at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRβ, however, has until recently been somewhat slower than that of its family members. ERRβ has also been largely ignored in summari ...[more]

PMID: 27507929

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The orphan nuclear receptor estrogen-related receptor beta (ERRβ) in triple-negative breast cancer.

Project description:PurposeTriple-negative breast cancer (TNBC)/basal-like breast cancer (BLBC) is a highly aggressive form of breast cancer. We previously reported that a small molecule agonist ligand for the orphan nuclear receptor estrogen-related receptor beta (ERRβ or ESRRB) has growth inhibitory and anti-mitotic activity in TNBC cell lines. In this study, we evaluate the association of ESRRB mRNA, copy number levels, and protein expression with demographic, clinicopathological, and gene expression features in breast tumor clinical specimens.MethodsESRRB mRNA-level expression and clinical associations were analyzed using RNAseq data. Array-based comparative genomic hybridization determined ESRRB copy number in African-American and Caucasian women. Transcription factor activity was measured using promoter-reporter luciferase assays in TNBC cell lines. Semi-automatic quantification of immunohistochemistry measured ERRβ protein expression on a 150-patient tissue microarray series.ResultsESRRB mRNA expression is significantly lower in TNBC/BLBC versus other breast cancer subtypes. There is no evidence of ESRRB copy number loss. ESRRB mRNA expression is correlated with the expression of genes associated with neuroactive ligand-receptor interaction, metabolic pathways, and deafness. These genes contain G/C-rich transcription factor binding motifs. The ESRRB message is alternatively spliced into three isoforms, which we show have different transcription factor activity in basal-like versus other TNBC cell lines. We further show that the ERRβ2 and ERRβsf isoforms are broadly expressed in breast tumors at the protein level.ConclusionsDecreased ESRRB mRNA expression and distinct patterns of ERRβ isoform subcellular localization and transcription factor activity are key features in TNBC/BLBC.

| S-EPMC7153462 | biostudies-literature

Modulation of estrogen-related receptors subtype selectivity: Conversion of an ERRβ/γ selective agonist to ERRα/β/γ pan agonists.

Project description:Estrogen Related Receptors (ERRs) are key regulators of energy homeostasis and play important role in the etiology of metabolic disorders, skeletal muscle related disorders, and neurodegenerative diseases. Among the three ERR isoforms, ERRα emerged as a potential drug target for metabolic and neurodegenerative diseases. Although ERRβ/γ selective agonist chemical tools have been identified, there are no chemical tools that effectively target ERRα agonism. We successfully engineered high affinity ERRα agonism into a chemical scaffold that displays selective ERRβ/γ agonist activity (GSK4716), providing novel ERRα/β/γ pan agonists that can be used as tools to probe the physiological roles of these nuclear receptors. We identified the structural requirements to enhance selectivity toward ERRα. Molecular modeling shows that our novel modulators have favorable binding modes in the LBP of ERRα and can induce conformational changes where Phe328 that originally occupies the pocket is dislocated to accommodate the ligands in a rather small cavity. The best agonists up-regulated the expression of target genes PGC-1α and PGC-1β, which are necessary to achieve maximal mitochondrial biogenesis. Moreover, they increased the mRNA levels of PDK4, which play an important role in energy homeostasis.

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Role of Estrogen Receptor β, G-Protein Coupled Estrogen Receptor and Estrogen-Related Receptors in Endometrial and Ovarian Cancer.

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| S-EPMC6175495 | biostudies-literature

Photoperiod affects estrogen receptor alpha, estrogen receptor beta and aggressive behavior.

Project description:Estrogens have important effects on male and female social behavior. Despite growing knowledge of the anatomy and behavioral effects of the two predominant estrogen receptor subtypes in mammals (ERalpha and ERbeta), relatively little is known about how these receptors respond to salient environmental stimuli. Many seasonally breeding species respond to changing photoperiods that predict seasonal changes in resource availability. We characterized the effects of photoperiod on aggressive behavior in two species of Peromyscus that exhibit gonadal regression in short days. P. polionotus (old field mice) were more aggressive than P. maniculatus (deer mice) and both species were more aggressive in short days. We used immunocytochemistry and real-time polymerase chain reaction to characterize the effects of photoperiod on ERalpha and ERbeta expression. In both species ERalpha-immunoreactive staining in the posterior bed nucleus of the stria terminalis (BNST) was increased in short vs. long days. Both species had reduced ERbeta-immunoreactive expression in the posterior BNST in short days. In the medial amygdala ERbeta immunoreactivity was increased in long days for both species. Using real-time polymerase chain reaction on punch samples that included the BNST, we observed that ERalpha mRNA was increased and ERbeta mRNA was decreased in short days. These data suggest that the effects of photoperiod on ERalpha and ERbeta expression may thus have important behavioral consequences.

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Antibody validation in estrogen receptor beta research

Project description:Three antibodies targeting estrogen receptor beta were evaluated with respect to their specificity towards the target protein, by immunoprecipitation followed by LC-Orbitrap MS.

2017-06-16 | PXD005936 | Pride

Applicability of Anti-Human Estrogen Receptor β Antibody PPZ0506 for the Immunodetection of Rodent Estrogen Receptor β Proteins.

Project description:Several lines of controversial evidence concerning estrogen receptor β (ERβ) remain to be solved because of the unavailability of specific antibodies against ERβ. The recent validation analysis identified a monoclonal antibody (PPZ0506) with sufficient specificity against human ERβ. However, the specificity and cross-reactivity of PPZ0506 antibody against ERβ proteins from laboratory animals have not been confirmed. In the present study, we aimed to validate the applicability of PPZ0506 to rodent studies. The antibody exhibited specific cross-reactivity against mouse and rat ERβ proteins in immunoblot and immunocytochemical experiments using transfected cells. In immunohistochemistry for rat tissue sections, PPZ0506 showed immunoreactive signals in the ovary, prostate, and brain. These immunohistochemical profiles of rat ERβ proteins in rat tissues accord well with its mRNA expression patterns. Although the antibody was reported to show the moderate signals in human testis, no immunoreactive signals were observed in rat testis. Subsequent RT-PCR analysis revealed that this species difference in ERβ expression resulted from different expression profiles related to the alternative promoter usage between humans and rats. In conclusion, we confirmed applicability of PPZ0506 for rodent ERβ studies, and our results provide a fundamental basis for further examination of ERβ functions.

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Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay.

Project description:Congenital forms of hearing impairment can be caused by mutations in the estrogen related receptor beta (ESRRB) gene. Our initial linkage studies suggested the ESRRB locus is linked to high caries experience in humans.We tested for association between the ESRRB locus and dental caries in 1,731 subjects, if ESRRB was expressed in whole saliva, if ESRRB was associated with the microhardness of the dental enamel, and if ESRRB was expressed during enamel development of mice.Two families with recessive ESRRB mutations and DFNB35 hearing impairment showed more extensive dental destruction by caries. Expression levels of ESRRB in whole saliva samples showed differences depending on sex and dental caries experience.The common etiology of dental caries and hearing impairment provides a venue to assist in the identification of individuals at risk to either condition and provides options for the development of new caries prevention strategies, if the associated ESRRB genetic variants are correlated with efficacy.

| S-EPMC4112727 | biostudies-literature

A polymorphism in human estrogen-related receptor beta (ESRRβ) predicts audiometric temporary threshold shift.

Project description:ObjectiveA non-synonymous single nucleotide polymorphism (rs61742642; C to T, P386S) in the ligand-binding domain of human estrogen-related receptor beta (ESRRβ) showed possible association to noise-induced hearing loss (NIHL) in our previous study.DesignThis study was conducted to examine the effect of the ESRRβ rs61742642 T variant on temporary threshold shift (TTS). TTS was induced by 10 minutes of exposure to audiometric narrow-band noise centered at 2000 Hz. Hearing thresholds and distortion product otoacoustic emissions input output function (DP IO) at 2000, 3000, and 4000 Hz were measured before and after the noise exposure.Study sampleNineteen participants with rs61742642 CT genotype and 40 participants with rs61742642 CC genotype were recruited for the study.ResultsParticipants with the CT genotype acquired a significantly greater TTS without convincing evidence of greater DP IO temporary level shift (DPTLS) compared to participants with the CC genotype.ConclusionThe results indicated that the ESRRβ polymorphism is associated with TTS. Future studies were recommended to explore molecular pathways leading to increased susceptibility to NIHL.

| S-EPMC8559306 | biostudies-literature

Estrogen receptor related beta is expressed in human endometrium throughout the normal menstrual cycle.

Project description:BackgroundEstrogen receptor related beta (ERRbeta, ESRRB/NR3B2) is an orphan receptor that shares significant sequence homology with estrogen receptors ERalpha and ERbeta. ERR family members are reported to exhibit constitutive transcriptional activity; however, little is known about the biological function of ERRbeta. In an attempt to delineate its role, we examined expression of ERRbeta in normal human endometrium, a tissue that undergoes cyclic remodelling under the influence of estrogen and progesterone.MethodsWell-characterized endometrial tissue (n = 31), including full-thickness biopsies, was obtained from women with regular menstrual cycles. RT-PCR was used to measure mRNA encoding ERRbeta, the peroxisome proliferator activated receptor gamma coactivators (PGC)-1alpha and beta and to determine whether ERRbeta splice variant mRNAs were expressed. ERRbeta was immunolocalized using both single and double antibody immunohistochemistry.ResultsTotal ERRbeta mRNA appeared higher in proliferative phase samples but results did not reach significance. Transcripts corresponding to the long- and short-splice variants of ERRbeta as well as PGC1alpha and beta were detected but ERRbetaDelta10 was absent. ERRbeta protein was localized to cell nuclei within multiple endometrial cell types including the glands, stroma, endothelium and immune cells, including uterine natural killer (uNK) cells and macrophages. Fluorescent immunohistochemistry revealed that some cells co-expressed ERRbeta and ERalpha or ERbeta, for example, endothelial and uNK cells were ERRbeta+/ERbeta+.ConclusionsERRbeta mRNA and protein are expressed in healthy human endometrium. Further studies are warranted to characterize the functional impact of ERRbeta on endometrial biology.

| S-EPMC2583942 | biostudies-literature

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