Estrogen-related receptor alpha


Estrogen-related receptor alpha
Estrogen-related receptor alpha

PDB rendering based on 1lo1.
Identifiers
Symbols ESRRA; ERR1; ERRa; ERRalpha; ESRL1; NR3B1
External IDs OMIM601998 MGI1346831 HomoloGene20941 IUPHAR: NR3B1 GeneCards: ESRRA Gene
RNA expression pattern
PBB GE ESRRA 1487 at tn.png
PBB GE ESRRA 203193 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2101 26379
Ensembl ENSG00000173153 ENSMUSG00000024955
UniProt P11474 Q3U110
RefSeq (mRNA) NM_004451 NM_007953.2
RefSeq (protein) NP_004442 NP_031979.2
Location (UCSC) Chr 11:
64.07 – 64.08 Mb
Chr 19:
6.99 – 7 Mb
PubMed search [1] [2]

Estrogen-related receptor alpha (ERR-α), also known as NR3B1 (nuclear receptor subfamily 3, group B, member 1), is a nuclear receptor that in humans is encoded by the ESRRA (EStrogen Related Receptor Alpha) gene.[1][2]

Contents

Tissue distribution

ERR-α has wide tissue distribution but it is most highly expressed in tissue that preferentially use fatty acids as energy sources such as kidney, heart, cerebellum, intestine, and skeletal muscle.[3]

Function

The protein encoded by this gene is a nuclear receptor that is closely related to the estrogen receptor. This protein acts as a site-specific (consensus TNAAGGTCA) transcription regulator and has been also shown to interact with estrogen and the transcription factor TFIIB by direct protein-protein contact. The binding and regulatory activities of this protein have been demonstrated in the regulation of a variety of genes including lactoferrin, osteopontin, medium-chain acyl coenzyme A dehydrogenase (MCAD) and thyroid hormone receptor genes. A processed pseudogene of ESRRA is located on chromosome 13q12.1.[1]

Metabolism

ERR-α regulates genes involved in mitochondrial biogenesis,[4] gluconeogenesis,[5] oxidative phosphorylation,[6] and fatty acid metabolism.[7] Furthermore ERR-α knockout mice display impaired fat metabolism and absorption.[8]

Estrogen signaling

Estrogen receptor alpha (ER-α) and estrogen related receptor alpha (ERR-α) have been found to regulate many of the same genes.[9][10] Furthermore ERR-α appears to modulate the activity of ER-α in various tissues including breast, uterus, and bone.[11]

Ligands

No endogenous ligands of ERR-α have been identified to date, hence ERR-α is classified as an orphan receptor. In addition both biochemical and structural studies indicate that ERR-α is constitutively active in the absence of ligand.[12]ERR-α does, however, interact with the metabolic-inducible coactivator PGC1-α in its AF2 region which is sometimes referred to as the "protein ligand" of ERR-α.

The isoflavone phytoestrogens genistein and daidzein are non-selective ERR agonists,[13] while XCT790 has been identified as a potent and selective inverse agonist of ERR-α.[14]

See also

References

  1. ^ a b "Entrez Gene: ESRRA estrogen-related receptor alpha". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2101. 
  2. ^ Giguère V, Yang N, Segui P, Evans RM (January 1988). "Identification of a new class of steroid hormone receptors". Nature 331 (6151): 91–4. doi:10.1038/331091a0. PMID 3267207. 
  3. ^ Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ (August 2006). "Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network". Cell 126 (4): 789–99. doi:10.1016/j.cell.2006.06.049. PMID 16923397. 
  4. ^ Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (July 1999). "Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1". Cell 98 (1): 115–24. doi:10.1016/S0092-8674(00)80611-X. PMID 10412986. 
  5. ^ Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM' (September 2001). "Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1". Nature 413 (6852): 131–8. doi:10.1038/35093050. PMID 11557972. 
  6. ^ Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, Spiegelman BM (April 2004). "Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle". Proc. Natl. Acad. Sci. U.S.A. 101 (17): 6570–5. doi:10.1073/pnas.0401401101. PMC 404086. PMID 15100410. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=404086. 
  7. ^ Huss JM, Torra IP, Staels B, Giguère V, Kelly DP (October 2004). "Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle". Mol. Cell. Biol. 24 (20): 9079–91. doi:10.1128/MCB.24.20.9079-9091.2004. PMC 517878. PMID 15456881. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=517878. 
  8. ^ Luo J, Sladek R, Carrier J, Bader JA, Richard D, Giguère V (November 2003). "Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha". Mol. Cell. Biol. 23 (22): 7947–56. doi:10.1128/MCB.23.22.7947-7956.2003. PMC 262360. PMID 14585956. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=262360. 
  9. ^ Vanacker JM, Bonnelye E, Chopin-Delannoy S, Delmarre C, Cavaillès V, Laudet V (May 1999). "Transcriptional activities of the orphan nuclear receptor ERR alpha (estrogen receptor-related receptor-alpha)". Mol. Endocrinol. 13 (5): 764–73. doi:10.1210/me.13.5.764. PMID 10319326. http://mend.endojournals.org/cgi/pmidlookup?view=long&pmid=10319326. 
  10. ^ Vanacker JM, Pettersson K, Gustafsson JA, Laudet V (August 1999). "Transcriptional targets shared by estrogen receptor- related receptors (ERRs) and estrogen receptor (ER) alpha, but not by ERbeta". Embo J. 18 (15): 4270–9. doi:10.1093/emboj/18.15.4270. PMC 1171503. PMID 10428965. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1171503. 
  11. ^ Stein RA, McDonnell DP (December 2006). "Estrogen-related receptor alpha as a therapeutic target in cancer". Endocr. Relat. Cancer 13 Suppl 1: S25–32. doi:10.1677/erc.1.01292. PMID 17259555. 
  12. ^ Kallen J, Schlaeppi JM, Bitsch F, Filipuzzi I, Schilb A, Riou V, Graham A, Strauss A, Geiser M, Fournier B (November 2004). "Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha". J. Biol. Chem. 279 (47): 49330–7. doi:10.1074/jbc.M407999200. PMID 15337744. 
  13. ^ Suetsugi M, Su L, Karlsberg K, Yuan YC, Chen S (November 2003). "Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors". Mol. Cancer Res. 1 (13): 981–91. PMID 14638870. http://mcr.aacrjournals.org/cgi/pmidlookup?view=long&pmid=14638870. 
  14. ^ Busch BB, Stevens WC Jr, Martin R, Ordentlich P, Zhou S, Sapp DW, Horlick RA, Mohan R (November 2004). "Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha". J. Med. Chem. 47 (23): 5593–6. doi:10.1021/jm049334f. PMID 15509154. 

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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