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ESRRA (estrogen-related receptor alpha)

Written2009-07Rebecca Stein Kunder, Donald P McDonnell
Department of Pharmacology, Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesESRL1
Alias_symbol (synonym)ERR1
ERRalpha
NR3B1
ERRa
Other aliasERR-alpha
HGNC (Hugo) ESRRA
LocusID (NCBI) 2101
Atlas_Id 44408
Location 11q13.1  [Link to chromosome band 11q13]
Location_base_pair Starts at 64306227 and ends at 64316740 bp from pter ( according to hg19-Feb_2009)  [Mapping ESRRA.png]
Fusion genes
(updated 2016)
ESRRA (11q13.1) / TEX40 (11q13.1)
Note -Size: 11,172 bases;
-Orientation: plus strand.

DNA/RNA

Description -Sequence length 11,172 bases;
-CDS: 2221;
-Exons: 7.
Transcription Alternative splicing results in transcript variants, but these have not yet been well-characterized.
Pseudogene A pseudogene has been reported, ESRRAP, located at 13q12.1. However, it is possible that this pseudogene is not transcribed (Sladek et al., 1997).

Protein

 
  Schematic of nuclear receptor structure and function.
ERRa is a member of the nuclear receptor (NR) superfamily of transcription factors and is most closely related to estrogen receptor alpha (ERa). The modular structure of NRs consists of seven (A-F) domains. The A/B region, which harbors activation function 1 (AF-1), is not well-conserved across NRs, but regions C and E are highly conserved and harbor, respectively, the DNA-binding domain (DBD) and ligand-binding domain (LBD). ERRa shares with ERa 68% sequence identity within the DBD and 33% within the LBD. The functional regions of the DBD have been finely mapped. In addition to two zinc finger motifs, this domain contains a Proximal-box (P-box) which determines DNA sequence specificity, and a Dimerization-box (D-box), which part of the dimerization interface.
Description ERRa is a 45.5 kDa, 423 amino acid orphan nuclear receptor. Although closely related to the estrogen receptors, its transcriptional activity is regulated to any significant degree by estrogens. ERRa binds to specific DNA sequences within target gene promoters as a monomer or homodimer and recruits coactivating proteins, the best known of which is PGC-1a.
Expression ERRa is ubiquitously expressed throughout development with the highest levels of expression in tissues that oxidize fatty acids such as kidney, heart, cerebellum, intestine and skeletal muscle (nursa).
Localisation ERRa is thought to be predominately nuclear, although recently it has been reported to be perinuclear and cytoplasmic in breast cancer tissue (Jarzabek et al., 2009).
Function The function of ERRa as a metabolic regulator is supported by the observation that erra-null mice demonstrate impaired fat metabolism and absorption (Luo et al., 2003). It has recently been demonstrated that erra-null mice also have a reduced capacity for adaptation to hemodynamic stressors. Due to this functional deficit, these mice often develop cardiac contractile dysfunction. The cardiac remodeling under stress in ERR-null mice is due to defects in ATP synthesis and reduced phosphocreatine stores, which are both characteristic of pathologic cardiac hypertrophy (Huss et al., 2007). That the expression of ERRa is elevated in exercising muscle and in fasting liver specifically implicates this receptor in beta-oxidation of fatty acids, a metabolic pathway that is highly active under these conditions. On a mechanistic level, several studies have revealed that ERRa is involved in the transcriptional regulation of genes required for mitochondrial biogenesis, oxidative phosphorylation and fatty acid oxidation (Huss et al., 2004; Mootha et al., 2004; Dufour et al., 2007).
Thus far, metabolic studies of ERRa function have mainly focused on its role as the downstream effector of PGC-1a. PGC-1a is a promiscuous nuclear receptor coactivator expressed at low basal levels but induced by fasting and other metabolic stresses (Puigserver and Spiegelman, 2003). PGC-1beta, a related cofactor, may have similar functions, although its expression level is not as acutely regulated by variations in energy demand (Yoon et al., 2001). Rather than being regulated by ligand, the magnitude of ERRa activity is thought to be largely dependent on the presence of transcriptional coactivators such as PGC-1a and beta. Interest in the ERR-PGC-1 regulatory axis was heightened by the observation that there is a decrease in both PGC-1a and PGC-1beta in the skeletal muscle of patients with diabetes and obesity (Mootha et al., 2003).
Homology Sequence analysis reveals that the ERRs and the classical estrogen receptors share a high degree of homology within their DNA and ligand binding domains. In particular, ERRa shares with ERa approximately 68% sequence identity within the DNA binding domain and 33% within the ligand binding domains. This relationship provides a structural basis both for the conserved nature of DNA binding and the divergence in hormone binding between these two receptors.

Mutations

Note Although over 80 SNPs have been reported, only one variant has been shown to carry clinical associations.
Laflamme et al. reported a polymoprohic hormone response element within the ESRRA promoter (Laflamme et al., 2005). The variant sequence, present in 11% of the population tested (white, premenopausal women), included an ERRa responsive element within the additional 23-nucelotides. This longer variant was associated with higher bone mineral density measured in the lumbar spine.
Kamei et al. reported that the longer variant is associated with a significantly higher body mass index in their study population of 729 Japanese men and women (Kamie et al., 2005).

Implicated in

Note
  
Entity Breast cancer
Prognosis Two independent clinical studies have implicated ERRa in breast cancer progression (Ariazi et al., 2002; Suzuki et al., 2004). In the first study to link ERRa to clinical and pathological characteristics of breast cancer, Ariazi et al. found that ERRa expression is significantly associated with ERa-negative and progesterone receptor-negative tumor status as well as Her2 status. Further exploring the relationship between ERRa and Her2, Barry et al. demonstrated that ERRa transcriptional activity can be enhanced by phosphorylation events downstream of Her2 (Barry and Giguere, 2005). Building on the association between ERRa and negative prognostic biomarkers, Suzuki et al. demonstrated a direct correlation between ERRa expression and unfavorable breast cancer patient outcomes including increased tumor recurrence and decreased survival (Suzuki et al., 2004). Importantly, the predictive value of ERRa expression was shown to be independent of ERa status, confirming that targeting the ERRa pathway may be of therapeutic benefit in patients with either ERa-positive or ERa-negative breast cancer.
Recently, the function of ERRa has been evaluated in xenograft models of breast cancer. Stein et al. demonstrated that ERRa is critical for the growth of ERa-negative breast cancer through use of RNAi (Stein et al. 2008). Furthermore, Chisamore and coworkers found that an ERRa antagonist inhibited the growth of ERa-positive and ERa-negative breast cancer cell lines in a xenograft model (Chisamore et al., 2009).
  
  
Entity Ovarian cancer
Prognosis Sun et al. demonstrated that the ovarian tumors had significantly higher ERRa mRNA levels than normal ovaries and that high ERRa expression correlated with clinically advanced and histologically aggressive disease. Furthermore, ERRa expression was shown to be an independent prognostic factor for poor overall patient survival (Sun et al., 2005).
  
  
Entity Colorectal cancer
Prognosis Analysis of 80 colorectal tumor samples demonstrated that higher levels of ERRa mRNA are expressed in tumor tissue versus in the surrounding normal mucosa. Furthermore, tumor tissue ERRa mRNA levels are positively correlated with increased tumor stage and histological grade (Cavallini et al., 2005).
  
  
Entity Prostate cancer
Prognosis Cheung et al. investigated the expression patterns of the three ERR family members in normal and malignant human prostate epithelial cells and cell lines (Cheung et al., 2005). The authors also characterized ERR protein expression and localization in normal, dysplastic, and malignant prostate tissue (Cheung et al., 2005). They concluded that ERRbeta and ERRgamma protein expression is reduced in neoplastic prostatic cells versus their non-malignant counterparts and suggested that each is down-regulated in the progression of prostate cancer. The authors went on to measure the effect of overexpressing the ERRs on proliferation of an immortalized prostate cell line and a prostate cancer cell line in vitro and on prostate cancer xenograft growth in vivo (Yu et al., 2007; Yu et al., 2008). They found that ERRbeta and ERRgamma can inhibit proliferation in cells derived from normal and malignant prostate epithelium by inducing a G1-S cell cycle arrest. Furthermore, activation of either ERRbeta or ERRgamma using the agonist DY131 resulted in a decreased rate of prostate tumor growth in a xenograft model.
  
  
Entity Endometrial cancer
Prognosis Gao et al. explored the extent to which the ERRs are involved in ERa-positive endometrial adenocarcinoma (Gao et al., 2006). They measured the expression of each ERR family member in malignant versus normal endometrium and compared the expression levels to clinical and pathologic features. They concluded that the expression of ERRa mRNA was lower in ERa-positive endometrial adenocarcinoma versus normal endometrium. However, they also found that ERRa mRNA expression was positively correlated with tumor stage and myometrial invasion. Additionally Gao et al. found that the expression of ERRgamma mRNA was increased in endometrial adenocarcinoma compared to normal endometrium.
  

Breakpoints

Note None.

To be noted

In the absence of known endogenous ligand, considerable effort has been made toward identifying small molecules to modulate ERRa activity. Several ERRa antagonists have been developed and recently a novel antagonist was described that inhibited the growth of breast cancer xenografts (Chisamore et al., 2009).

Bibliography

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Citation

This paper should be referenced as such :
Stein, Kunder R ; McDonnell, DP
ESRRA (estrogen-related receptor alpha)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(6):555-559.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/ESRRAID44408ch11q13.html


External links

Nomenclature
HGNC (Hugo)ESRRA   3471
Cards
AtlasESRRAID44408ch11q13
Entrez_Gene (NCBI)ESRRA  2101  estrogen related receptor alpha
AliasesERR1; ERRa; ERRalpha; ESRL1; 
NR3B1
GeneCards (Weizmann)ESRRA
Ensembl hg19 (Hinxton)ENSG00000173153 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000173153 [Gene_View]  chr11:64306227-64316740 [Contig_View]  ESRRA [Vega]
ICGC DataPortalENSG00000173153
TCGA cBioPortalESRRA
AceView (NCBI)ESRRA
Genatlas (Paris)ESRRA
WikiGenes2101
SOURCE (Princeton)ESRRA
Genetics Home Reference (NIH)ESRRA
Genomic and cartography
GoldenPath hg38 (UCSC)ESRRA  -     chr11:64306227-64316740 +  11q13.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ESRRA  -     11q13.1   [Description]    (hg19-Feb_2009)
EnsemblESRRA - 11q13.1 [CytoView hg19]  ESRRA - 11q13.1 [CytoView hg38]
Mapping of homologs : NCBIESRRA [Mapview hg19]  ESRRA [Mapview hg38]
OMIM601998   
Gene and transcription
Genbank (Entrez)AB362579 BC007915 BC011528 BC033701 BC063795
RefSeq transcript (Entrez)NM_001282450 NM_001282451 NM_004451
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)ESRRA
Cluster EST : UnigeneHs.110849 [ NCBI ]
CGAP (NCI)Hs.110849
Alternative Splicing GalleryENSG00000173153
Gene ExpressionESRRA [ NCBI-GEO ]   ESRRA [ EBI - ARRAY_EXPRESS ]   ESRRA [ SEEK ]   ESRRA [ MEM ]
Gene Expression Viewer (FireBrowse)ESRRA [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2101
GTEX Portal (Tissue expression)ESRRA
Protein : pattern, domain, 3D structure
UniProt/SwissProtP11474   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP11474  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP11474
Splice isoforms : SwissVarP11474
PhosPhoSitePlusP11474
Domaine pattern : Prosite (Expaxy)NUCLEAR_REC_DBD_1 (PS00031)    NUCLEAR_REC_DBD_2 (PS51030)   
Domains : Interpro (EBI)Nucl_hrmn_rcpt_lig-bd    Nuclear_hrmn_rcpt    Oest-rel_rcp    Oest_rcpt/oest-rel_rcp    Znf_hrmn_rcpt    Znf_NHR/GATA   
Domain families : Pfam (Sanger)Hormone_recep (PF00104)    zf-C4 (PF00105)   
Domain families : Pfam (NCBI)pfam00104    pfam00105   
Domain families : Smart (EMBL)HOLI (SM00430)  ZnF_C4 (SM00399)  
Conserved Domain (NCBI)ESRRA
DMDM Disease mutations2101
Blocks (Seattle)ESRRA
PDB (SRS)1XB7    2PJL    3D24    3K6P   
PDB (PDBSum)1XB7    2PJL    3D24    3K6P   
PDB (IMB)1XB7    2PJL    3D24    3K6P   
PDB (RSDB)1XB7    2PJL    3D24    3K6P   
Structural Biology KnowledgeBase1XB7    2PJL    3D24    3K6P   
SCOP (Structural Classification of Proteins)1XB7    2PJL    3D24    3K6P   
CATH (Classification of proteins structures)1XB7    2PJL    3D24    3K6P   
SuperfamilyP11474
Human Protein AtlasENSG00000173153
Peptide AtlasP11474
HPRD07210
IPIIPI00792208   IPI00005717   IPI00430773   IPI01009499   IPI01015915   IPI01015488   
Protein Interaction databases
DIP (DOE-UCLA)P11474
IntAct (EBI)P11474
FunCoupENSG00000173153
BioGRIDESRRA
STRING (EMBL)ESRRA
ZODIACESRRA
Ontologies - Pathways
QuickGOP11474
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding  fibrillar center  DNA binding  steroid hormone receptor activity  RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding  steroid binding  protein binding  nucleus  nucleoplasm  regulation of transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  mitochondrion organization  zinc ion binding  microtubule cytoskeleton  protein domain specific binding  intracellular receptor signaling pathway  response to estradiol  regulation of cell proliferation  steroid hormone mediated signaling pathway  sequence-specific DNA binding  intercellular bridge  regulation of osteoblast differentiation  regulation of osteoclast differentiation  positive regulation of transcription from RNA polymerase II promoter  cartilage development  positive regulation of cellular response to insulin stimulus  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding  fibrillar center  DNA binding  steroid hormone receptor activity  RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding  steroid binding  protein binding  nucleus  nucleoplasm  regulation of transcription, DNA-templated  transcription initiation from RNA polymerase II promoter  mitochondrion organization  zinc ion binding  microtubule cytoskeleton  protein domain specific binding  intracellular receptor signaling pathway  response to estradiol  regulation of cell proliferation  steroid hormone mediated signaling pathway  sequence-specific DNA binding  intercellular bridge  regulation of osteoblast differentiation  regulation of osteoclast differentiation  positive regulation of transcription from RNA polymerase II promoter  cartilage development  positive regulation of cellular response to insulin stimulus  
Pathways : BIOCARTARegulation of PGC-1a [Genes]   
REACTOMEP11474 [protein]
REACTOME PathwaysR-HSA-383280 [pathway]   
NDEx NetworkESRRA
Atlas of Cancer Signalling NetworkESRRA
Wikipedia pathwaysESRRA
Orthology - Evolution
OrthoDB2101
GeneTree (enSembl)ENSG00000173153
Phylogenetic Trees/Animal Genes : TreeFamESRRA
HOVERGENP11474
HOGENOMP11474
Homologs : HomoloGeneESRRA
Homology/Alignments : Family Browser (UCSC)ESRRA
Gene fusions - Rearrangements
Fusion : MitelmanESRRA/TEX40 [11q13.1/11q13.1]  
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerESRRA [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ESRRA
dbVarESRRA
ClinVarESRRA
1000_GenomesESRRA 
Exome Variant ServerESRRA
ExAC (Exome Aggregation Consortium)ESRRA (select the gene name)
Genetic variants : HAPMAP2101
Genomic Variants (DGV)ESRRA [DGVbeta]
DECIPHERESRRA [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisESRRA 
Mutations
ICGC Data PortalESRRA 
TCGA Data PortalESRRA 
Broad Tumor PortalESRRA
OASIS PortalESRRA [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICESRRA  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDESRRA
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ESRRA
DgiDB (Drug Gene Interaction Database)ESRRA
DoCM (Curated mutations)ESRRA (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ESRRA (select a term)
intoGenESRRA
NCG5 (London)ESRRA
Cancer3DESRRA(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601998   
Orphanet
MedgenESRRA
Genetic Testing Registry ESRRA
NextProtP11474 [Medical]
TSGene2101
GENETestsESRRA
Target ValidationESRRA
Huge Navigator ESRRA [HugePedia]
snp3D : Map Gene to Disease2101
BioCentury BCIQESRRA
ClinGenESRRA
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2101
Chemical/Pharm GKB GenePA27887
Clinical trialESRRA
Miscellaneous
canSAR (ICR)ESRRA (select the gene name)
Probes
Litterature
PubMed141 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineESRRA
EVEXESRRA
GoPubMedESRRA
iHOPESRRA
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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