DEFINITION
There are three known estrogen related receptors:
The ERRs are members of the nuclear receptor family.
ERR's bind to estrogen response elements on DNA and modulate transcription but do not bind to endogenous estrogens.
In addition, ERR's seem to have their own response elements termed ERRE's. ERR's have been shown to play a role in energy homeostasis and cancer.
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
It is very similar to ER (68% similarity)
Protein Aminoacids Percentage
SYNTHESIS AND TURNOVER
mRNA synthesis
Hypoxia
Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7821-6. Epub 2008 May 28.
Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors. 2008
Ao A, Wang H, Kamarajugadda S, Lu J.
Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, P.O. Box 103633, Gainesville, FL 32610, USA.
Abstract
The development of intratumoral hypoxia is a universal hallmark of rapidly growing solid tumors. Adaptation to the hypoxic environment, which is critical for tumor cell survival and growth, is mediated primarily through a hypoxia-inducible factor (HIF)-dependent transcriptional program. HIF activates genes that facilitate crucial adaptive mechanisms including increased glucose uptake and glycolysis and tumor angiogenesis, making it an important therapeutic target. However, the HIF-dependent transcriptional mechanism remains incompletely understood, and targeting HIF is a difficult endeavor. Here, we show that the orphan nuclear receptor estrogen-related receptors (ERRs) physically interact with HIF and stimulate HIF-induced transcription. Importantly, ERRs appear to be essential for HIF's function. Transcriptional activation of hypoxic genes in cells cultured under hypoxia is largely blocked by suppression of ERRs through expression of a dominant negative form of ERR or treatment with a pharmacological ERR inhibitor, diethylstilbestrol. Systematic administration of diethylstilbestrol severely diminished growth and angiogenesis of tumor xenografts in vivo. Because nuclear receptors are outstanding targets for drug discovery, the findings not only may offer mechanistic insights into HIF-mediated transcription but also may open new avenues for targeting the HIF pathway for cancer therapy.
Nature. 2008 Feb 21;451(7181):1008-12.
"HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha.":
Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Chinsomboon J, Rangwala SM, Baek KH, Rosenzweig A, Spiegelman BM.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. zarany1@partners.org
Abstract
Ischaemia of the heart, brain and limbs is a leading cause of morbidity and mortality worldwide. Hypoxia stimulates the secretion of vascular endothelial growth factor (VEGF) and other angiogenic factors, leading to neovascularization and protection against ischaemic injury. Here we show that the transcriptional coactivator PGC-1alpha (peroxisome-proliferator-activated receptor-gamma coactivator-1alpha), a potent metabolic sensor and regulator, is induced by a lack of nutrients and oxygen, and PGC-1alpha powerfully regulates VEGF expression and angiogenesis in cultured muscle cells and skeletal muscle in vivo. PGC-1alpha-/- mice show a striking failure to reconstitute blood flow in a normal manner to the limb after an ischaemic insult, whereas transgenic expression of PGC-1alpha in skeletal muscle is protective. Surprisingly, the induction of VEGF by PGC-1alpha does not involve the canonical hypoxia response pathway and hypoxia inducible factor (HIF). Instead, PGC-1alpha coactivates the orphan nuclear receptor ERR-alpha (oestrogen-related receptor-alpha) on conserved binding sites found in the promoter and in a cluster within the first intron of the VEGF gene. Thus, PGC-1alpha and ERR-alpha, major regulators of mitochondrial function in response to exercise and other stimuli, also control a novel angiogenic pathway that delivers needed oxygen and substrates. PGC-1alpha may provide a novel therapeutic target for treating ischaemic diseases.
protein synthesis
post-translational modifications
degradation
PGC-1alpha, un co-activateur transcriptionnel impliqué dans le métabolisme
PGC-1alpha, co-activator activity is inhibited by ERRalpha
CELLULAR FUNCTIONS
cellular localization,
biological function
ERRα
- regulation of a variety of genes including lactoferrin, osteopontin, medium-chain acyl coenzyme A dehydrogenase (MCAD) and thyroid hormone receptor genes.
ERRα could increase oxidative metabolism through higher sensitivity to Thyroid Hormone
- Genomic Convergence among ERRα, PROX1, and BMAL1 in the Control of Metabolic Clock Outputs, 2011
- Suppressing the activity of ERRalpha in 3T3-L1 adipocytes reduces mitochondrial biogenesis but enhances glycolysis and basal glucose uptake. 2008
- The role of ERRalpha in mitochondrial function and insulin resistance, 2006
We expect to demonstrate that ERRa regulates muscle mitochondrial metabolism and plays an important role in the development of the insulin resistance that precedes type 2 diabetes.
- Physiological genomics identifies estrogen-related receptor alpha as a regulator of renal sodium and potassium homeostasis and the renin-angiotensin pathway. 2009 Estrogen-related receptor alpha (ERRalpha) is an orphan nuclear receptor highly expressed in the kidney, an organ playing a central role in blood pressure regulation through electrolyte homeostasis and the renin-angiotensin system. Physiological analysis revealed that, relative to wild-type mice, ERRalpha null mice are hypotensive despite significant hypernatremia, hypokalemia, and slight hyperreninemia. Using a combination of genome-wide location analysis and expression profiling, we demonstrate that ERRalpha regulates the expression of channels involved in renal Na(+) and K(+) handling (Scnn1a, Atp1a1, Atp1b1) and altered in Bartter syndrome (Bsnd, Kcnq1). In addition, ERRalpha regulates the expression of receptors implicated in the systemic regulation of blood pressure (Ghr, Gcgr, Lepr, Npy1r) and of genes within the renin-angiotensin pathway (Ren1, Agt, Ace2). Our study thus identifies ERRalpha as a pleiotropic regulator of renal control of blood pressure, renal Na(+)/K(+) homeostasis, and renin-angiotensin pathway and suggests that modulation of ERRalpha activity could represent a potential avenue for the management of hypertension.
- Absence of ERRalpha in female mice confers resistance to bone loss induced by age or estrogen-deficiency, 2009
- Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. 2003
ERRβ
ERRγ
- There is evidence that bisphenol A functions as an endocrine disruptor by binding strongly to ERR-γ. BPA seems to binds strongly to ERR-γ (dissociation constant = 5.5 nM), but not to the estrogen receptor (ER). BPA binding to ERR-γ preserves its basal constitutive activity. It can also protect it from deactivation from the selective estrogen receptor modulator 4-hydroxytamoxifen.
ERR and collagen
Estrogen receptor-related receptor-alpha (ERR-alpha) is dysregulated in inflammatory arthritis. 2008
REGULATION
DIAGNOSTIC USE
