3115 - J. Clin. Endocrinol. Metab. 2005 90:3115-3121...

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Unformatted text preview: J. Clin. Endocrinol. Metab. 2005 90:3115-3121 originally published online Feb 15, 2005; , doi: 10.1210/jc.2004-2168 E. Bonnelye and J. E. Aubin in Bone Estrogen Receptor-Related Receptor {alpha}: A Mediator of Estrogen Response Society please go to: http://jcem.endojournals.org//subscriptions/ or any of the other journals published by The Endocrine Journal of Clinical Endocrinology & Metabolism To subscribe to Copyright The Endocrine Society. All rights reserved. Print ISSN: 0021-972X. Online REVIEW: Estrogen Receptor-Related Receptor : A Mediator of Estrogen Response in Bone E. Bonnelye and J. E. Aubin Department of Molecular and Medical Genetics, University of Toronto, Toronto M5S 1A8, Canada Estrogen receptor-related receptor- (ERR ) is an orphan nu- clear receptor with sequence homology to the estrogen recep- tors, ER / , but it does not bind estrogen. However, several recent studies suggest that ERR not only plays a functional role in osteoblasts but also impinges on the estrogen axis in bone,asitdoesinatleastcertainotherestrogentargettissues. We summarize here data on ERR and its cellular and mo- lecular modes of action that have broad implications for con- sidering the potential role of this orphan receptor as a new therapeutic target in osteopenic disorders such as osteopo- rosis as well as other estrogen-responsive conditions. ( J Clin Endocrinol Metab 90: 31153121, 2005) T HE PLEIOTROPIC EFFECTS of estradiol are transduced by two receptors known as estrogen receptor (ER)- and ER [NR3A1 and NR3A2, respectively, according to the Nuclear Receptors Nomenclature Committee (1)], which be- long to the superfamily of nuclear receptors (2, 3). The nu- clear receptors are transcription factors comprising both ligand-dependent molecules ( e.g. steroid hormone, thyroid hormone, retinoic acid, and vitamin D receptors) and a large number of so-called orphan receptors for which ligands have not been identified (4, 5). The first orphan nuclear receptors identified were proteins related to ER and were referred to as ER-related receptors (ERRs) (6). ERR and ERR (NR3B1 and NR3B2) were iden- tified by low-stringency screening of cDNA libraries with a probe encompassing the DNA binding domain of human ER . A third ERR, ERR , was identified by yeast two-hybrid screening with the glucocorticoid receptor-interacting pro- tein 1 as bait (7). The DNA-binding domain of ERRs and ERs is highly conserved; however, other parts of the proteins share very little homology (6, 7). Thus, sequence alignment of ERR and the ERs reveals a high similarity (68%) in the DNA-binding domain and a moderate similarity (36%) in the ligand-binding E domain, which may explain the fact that ERR does not bind estrogen. Nevertheless, considerable data support the idea that ERR may impinge on the estro- gen pathway. ERR interacts with ERs through protein-pro- tein interactions in vitro and recognizes the same DNA bind- ing element as ERs (8, 9). ERR , ERR , and ER can bind to and activate transcription through both the functional estro-...
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3115 - J. Clin. Endocrinol. Metab. 2005 90:3115-3121...

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