Disease relevance of ESRRA

• Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer [1].
• We observed increased expression of hERRalpha mRNA (P = 0.020) and hERRgamma mRNA (P = 0.045) in ovarian cancers compared to normal ovaries [2].
• Mutation and deletion analyses revealed that a 53 bp region containing repeated core element AGGTCA motifs of the ERRalpha gene serves as a multi-hormone response element (MHRE) for several nuclear receptors in transient co-transfection studies of human endometrial carcinoma (HEC-1B) cells [3].
• Here we report that ERRalpha and ERRgamma stimulate the PDK4 gene in hepatoma cells, suggesting a novel role for ERRs in controlling pyruvate metabolism [4].
• This effect is cell-specific since ERR-1 activates transcription in the rat osteosarcoma cell line ROS 17.2/8 as well as in HeLa, NB-E, and FREJ4 cells but not in COS1 and HepG2 cells [5].
• ERRalpha immunoreactivity was detected in the nuclei of aldosterone producing adenoma (APA), cortisol producing adenoma (CPA) and adrenocortical carcinoma (ACC), and higher average mRNA levels of ERRα were detected in ACC when compared to APA, CPA and normal adrenal cortex [6].

High impact information on ESRRA

• Partial amino acid sequence data obtained from the approximately 55-kD component of IBP-s indicate that it is hERR1, an orphan member of the steroid-thyroid hormone receptor superfamily [7].
• In this study, we describe the customization of PGC-1alpha and its use to study the biology of the estrogen-related receptor alpha (ERRalpha) in cultured liver cells [8].
• Starting from this apparent contradiction, we have evaluated the potentials of two related receptors ERRalpha and ERRbeta to intervene in estrogen signaling [9].
• Our findings demonstrate that ERRalpha is a key regulator of mitochondrial biogenesis and oxidative metabolism, and essential for adaptive thermogenesis [10].
• Rather, we show that ERRalpha is needed for the high levels of mitochondrial biogenesis and oxidative capacity characteristic of brown adipose tissue (BAT), and thus for providing the energy necessary for thermogenesis [10].
• In normal adrenal cortex tissues, ERRalpha expression is possibly related to adrenal development, playing a role in fetal adrenal function, in DHEAS production in adrenarche, and also in steroid production of post-adrenarche/adult life [6].

Chemical compound and disease context of ESRRA

• Finally, we demonstrate that ERRalpha is the major isoform expressed in human breast cancer cell lines and that diethylstilbestrol can inhibit the growth of both ER-positive and -negative cell lines [11].
• ERRalpha modulates estrogen-induced activity in estrogen-dependent endometrial cancer [12].
• ERRalpha is also a phosphoprotein whose expression in human breast tumors correlates with that of the receptor tyrosine kinase ErbB2, suggesting that its transcriptional activity could be regulated by signaling cascades [13].

Biological context of ESRRA

• Strikingly, introduction of PGC-1alpha in HeLa cells by transient transfection induces the activity of the ESRRA promoter in a manner that is dependent on the presence of the ESRRA23 element and on its dosage [14].
• All bone measures were tested separately for association with the ESRRA genotype by analysis of covariance [15].
• Using fluorescence in situ hybridization, we have mapped the human ESRRA gene to chromosome 11q12-q13 and the human ESRRB gene to chromosome 14q24 [16].
• ERR alpha was initially isolated based on its sequence homology to the estrogen receptor but is not activated by classic estrogens [17].
• We show that the major isoform of the human ERRalpha gene, ERRalpha1, can sequence-specifically bind a consensus palindromic estrogen response element (ERE) and directly compete with estrogen receptor alpha (ERalpha) for binding [18].

Anatomical context of ESRRA

• However, no association was observed between ESRRA and QUS heel bone measures [15].
• The crystal structure of the ligand binding domain (LBD) of the estrogen-related receptor alpha (ERRalpha, NR3B1) complexed with a coactivator peptide from peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) reveals a transcriptionally active conformation in the absence of a ligand [19].
• RT-PCR showed that ERRalpha and ERRgamma transcripts were detected in most cell lines and xenografts, whereas ERRbeta was detected in normal epithelial cells and few immortalized cell lines but not in most cancer lines [20].
• To analyze the subcellular localization of ERRalpha, a green fluorescent protein (GFP)-reporter plasmid of hERRalpha was constructed and transfected into the ovarian cancer cell line OVCAR-3 [2].
• In experiments using ERRalpha null fibroblasts, the ability of PGC-1alpha to stimulate the ESRRA promoter is considerably reduced but can be restored by addition of ERRalpha [14].
• ERRalpha has been detected in fetal, post-birth, and adult human adrenocortex; in the fetal adrenal, a higher labeling index (LI) was detected in the neocortex (NC) ( 71.2 ± 4.99%), when compared to the fetal zone (FZ) (24.9 ± 5.17%) (P = 0.0017) [6].

Associations of ESRRA with chemical compounds

• The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene [17].
• Consequently, ERRalpha may potentiate constitutive transcription of estrogen response element-containing genes independently of ERalpha and antiestrogens in ErbB2-positive tumors [1].
• In addition, we show that a PGC-1alpha peptide containing this nuclear box motif from the L3 site binds ERRalpha LBD with a higher affinity than a peptide containing a steroid receptor coactivator-1 motif and that the affinity is further enhanced when all three leucine-rich regions of PGC-1alpha are present [19].
• Herein we test the hypothesis that ERRalpha regulates transcription of the genes encoding the enzymes involved in adrenal steroid production [21].
• The human estrogen-related receptor alpha 1 (hERR alpha 1) is an orphan member of the steroid/thyroid hormone receptor superfamily [22].

Physical interactions of ESRRA

• Second, PGC-1 interacts physically with ERRalpha and enables it to activate transcription [23].
• Finally, we show that the hERR1 interacts with the human estrogen receptor through protein-protein contacts [24].
• By gel mobility shift assay, the interaction of Ets1 with the downstream ERR-1-binding region was found to be more stable than its interaction with the upstream ERR-2 region [25].
• A single nucleotide in an estrogen-related receptor alpha site can dictate mode of binding and peroxisome proliferator-activated receptor gamma coactivator 1alpha activation of target promoters [26].
• In the present study, we demonstrate that TPA exerts this effect by enhancing the binding of the Sp1 transcription factor to an Sp1-binding site located within ERR-1 [27].

Enzymatic interactions of ESRRA

• Here, we investigated growth factor regulation of ERRalpha function and found that it is phosphorylated in MCF-7 breast cancer cells in response to epidermal growth factor (EGF), an event that enhances its DNA binding [13].

Regulatory relationships of ESRRA

• First, PGC-1 induces the expression of ERRalpha [23].
• Additionally, estrogen-related receptor alpha (ERRalpha) up-regulates MAO-B gene expression in breast cancer cells [28].
• We first show that RIP140 inhibits transactivation by ERRalpha, beta, and gamma on natural or artificial reporter genes containing different types of response elements [29].
• In contrast, heterodimerization with the related receptor ERRalpha inhibits the activities of both ERRgamma and ERRalpha [30].

Other interactions of ESRRA

• Estrogen-related receptor alpha 1 actively antagonizes estrogen receptor-regulated transcription in MCF-7 mammary cells [18].
• In this study, we show that the transcriptional coactivator PGC-1, which is implicated in the control of energy metabolism, regulates ERRalpha at two levels [23].
• Transcriptional regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) by estrogen-related receptor alpha [21].
• This study was conducted to determine whether human ERRalpha, ERRbeta, and ERRgamma might be involved in the tumorigenesis of ovarian cancer [2].
• We demonstrate that ERRalpha and ERRgamma up-regulate MAO-B gene activity, whereas ERalpha and ERbeta decrease stimulation in both a ligand-dependent and -independent manner [28].

Analytical, diagnostic and therapeutic context of ESRRA

• Real-time RT-PCR was first used to determine the levels of ERRalpha mRNA in various human tissues [21].
• Expression of ERRalpha in the adult adrenal was then confirmed using Western blotting and immunohistochemistry [21].
• Partial sequencing, restriction mapping, and PCR analysis revealed that the ESRL1 gene consists of seven exons and is approximately 20 kb in length [31].
• Survival analysis showed that the hERRalpha-positive group has a reduced overall survival (P = 0.015), and the ERRgamma-positive group has a longer progression-free survival (P = 0.020) [2].
• The ESRRA23 sequence contains a functional ERR response element that is specifically bound by ERRalpha, and chromatin immunoprecipitation shows that endogenous ERRalpha occupies its own promoter in vivo [14].

References