help button home button Endocrine Society Molecular Endocrinology ENDO 08 Sessions Library
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
This version published online on July 31, 2008
Molecular Endocrinology, doi:10.1210/me.2008-0041
Molecular Endocrinology Vol. 0, No. 2008 200800411-
doi:10.1210/me.2008-0041
Copyright © 2008 by the Endocrine Society.
This Article
Right arrow Author Manuscript (PDF)
Right arrow All Versions of this Article:
22/10/2241    most recent
Author Manuscript (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow NURSA Molecule Pages Link
Right arrow Request Copyright Permission
Google Scholar
Right arrow Articles by Phelan, C. A.
Right arrow Articles by Lazar, M. A.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Phelan, C. A.
Right arrow Articles by Lazar, M. A.

Submitted on February 1, 2008
Accepted on July 24, 2008

Selective Partial Agonism of Liver X Receptor {alpha} Is Related to Differential Corepressor Recruitment

Caroline A. Phelan, Joseph M. Weaver, David J. Steger, Shree Joshi, Jeffrey T. Maslany, Jon L. Collins, William J. Zuercher, Timothy M. Willson, Max Walker, Michael Jaye, and Mitchell A. Lazar*

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 USA; Discovery Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709-3398 USA; Cardiovascular and Urology Center of Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406 USA

* To whom correspondence should be addressed. E-mail: lazar{at}mail.med.upenn.edu.

Classically, activated transcription by nuclear receptors (NRs) is due to a ligand-induced switch from corepressor to coactivator bound states. However, coactivators and corepressors recognize overlapping surfaces of liganded and unliganded NRs, respectively. Here we show that, at sufficiently high concentration, the NR Corepressor (NCoR) influences the activity of the liver X receptor (LXR) even in the presence of a potent full agonist that destabilizes NCoR binding. Partial agonist ligands that less effectively dissociate NCoR from LXR are even more sensitive to NCoR levels, in a target-gene selective manner. Thus, differential recruitment of NCoR is a major determinant of partial agonism and selective LXR modulation of target genes.

NURSA Molecule Pages Link:

Nuclear Receptors:   LXRα  |  RXRα
Coregulators:   SRC-1  |  NCOR
Ligands:   T0901317  |  GW 3965





HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2008 by The Endocrine Society