help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
This version published online on December 4, 2003
Endocrinology, doi:10.1210/en.2003-1271
A more recent version of this article appeared on April 1, 2004
This Article
Right arrow Author Manuscript (PDF)
Right arrow All Versions of this Article:
145/4/1527    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 Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Agostini, M.
Right arrow Articles by Chatterjee, V K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Agostini, M.
Right arrow Articles by Chatterjee, V K.

Submitted on September 23, 2003
Accepted on November 24, 2003

TYROSINE AGONISTS REVERSE THE MOLECULAR DEFECTS ASSOCIATED WITH DOMINANT NEGATIVE MUTATIONS IN HUMAN PPAR{gamma}

Maura Agostini1, Mark Gurnell1, David B Savage1, Emily M Wood1, Aaron G Smith1, Odelia Rajanayagam1, Keith T Garnes1, Sidney H Levinson1, H Eric Xu1, John WR Schwabe1, Timothy M Willson1, Stephen O'Rahilly1, and V Krishna Chatterjee1*

1 Departments of Medicine and Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK; GlaxoSmithKline, Isotope Chemistry, Upper Merion, PA, USA; GlaxoSmithKline, Nuclear Receptor Discovery Research, Research Triangle Park, NC 27709, USA; Medical Research Council Laboratory of Molecular Biology, Addenbrooke's Hospital, Cambridge, CB2 2QH, UK

* To whom correspondence should be addressed. E-mail: kkc1{at}mole.bio.cam.ac.uk.

Loss-of-function mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) are associated with a novel syndrome characterized by partial lipodystrophy and severe insulin resistance. Here, we have further characterized the properties of natural dominant negative PPAR{gamma} mutants (P467L, V290M) and evaluated the efficacy of putative natural ligands and synthetic thiazolidinedione (TZD) or tyrosine-based (TA) receptor agonists in rescuing mutant receptor function. A range of natural ligands failed to activate the PPAR{gamma} mutants and their transcriptional responses to TZDs (e.g. pioglitazone, rosiglitazone) were markedly attenuated, whereas TAs (e.g. farglitazar) corrected defects in ligand binding and coactivator recruitment by the PPAR{gamma} mutants, restoring transcriptional function comparable to wild-type (WT) receptor. Transcriptional silencing via recruitment of corepressor contributes to dominant negative inhibition of WT by the P467L and V290M mutants and the introduction of an artificial mutation (L318A) disrupting corepressor interaction, abrogated their dominant negative activity. More complete ligand-dependent corepressor release and reversal of dominant negative inhibition was achieved with TA than TZD agonists. Modeling suggests a structural basis for these observations: both mutations destabilise helix 12 to favor receptor-corepressor interaction; conversely, farglitazar makes more extensive contacts than rosiglitazone within the ligand binding pocket, to stabilize helix 12, facilitating corepressor release and transcriptional activation. Farglitazar was a more potent inducer of PPAR{gamma} target gene (aP2) expression in peripheral blood mononuclear cells with the P467L mutation. Having shown that rosiglitazone is of variable and limited efficacy in these subjects, we suggest that TAs may represent a more rational therapeutic approach.
Key words: natural PPAR{gamma} mutants • tyrosine agonists • dominant negative inhibition • corepressor interaction




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
S. I. Anghel, E. Bedu, C. D. Vivier, P. Descombes, B. Desvergne, and W. Wahli
Adipose Tissue Integrity as a Prerequisite for Systemic Energy Balance: A CRITICAL ROLE FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR {gamma}
J. Biol. Chem., October 12, 2007; 282(41): 29946 - 29957.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
E. H. Jeninga, O. van Beekum, A. D. J. van Dijk, N. Hamers, B. I. Hendriks-Stegeman, A. M. J. J. Bonvin, R. Berger, and E. Kalkhoven
Impaired Peroxisome Proliferator-Activated Receptor {gamma} Function through Mutation of a Conserved Salt Bridge (R425C) in Familial Partial Lipodystrophy
Mol. Endocrinol., May 1, 2007; 21(5): 1049 - 1065.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
G. Li and T. Leff
Altered Promoter Recycling Rates Contribute to Dominant-Negative Activity of Human Peroxisome Proliferator-Activated Receptor-{gamma} Mutations Associated with Diabetes
Mol. Endocrinol., April 1, 2007; 21(4): 857 - 864.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
S. L. Gray, E. Dalla Nora, E. C. Backlund, M. Manieri, S. Virtue, R. C. Noland, S. O'Rahilly, R. N. Cortright, S. Cinti, B. Cannon, et al.
Decreased Brown Adipocyte Recruitment and Thermogenic Capacity in Mice with Impaired Peroxisome Proliferator-Activated Receptor (P465L PPAR{gamma}) Function
Endocrinology, December 1, 2006; 147(12): 5708 - 5714.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
L. Hansen, C. T. Ekstrom, R. Tabanera y Palacios, M. Anant, K. Wassermann, and R. R. Reinhardt
The Pro12Ala Variant of the PPARG Gene Is a Risk Factor for Peroxisome Proliferator-Activated Receptor-{gamma}/{alpha} Agonist-Induced Edema in Type 2 Diabetic Patients
J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3446 - 3450.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
A. G. Smith and G. E. O. Muscat
Orphan nuclear receptors: therapeutic opportunities in skeletal muscle
Am J Physiol Cell Physiol, August 1, 2006; 291(2): C203 - C217.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
A. Y. M. Au, C. McBride, K. G. Wilhelm Jr., R. J. Koenig, B. Speller, L. Cheung, M. Messina, J. Wentworth, V. Tasevski, D. Learoyd, et al.
PAX8-Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) Disrupts Normal PAX8 or PPAR{gamma} Transcriptional Function and Stimulates Follicular Thyroid Cell Growth
Endocrinology, January 1, 2006; 147(1): 367 - 376.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Yu, K. Markan, K. A. Temple, D. Deplewski, M. J. Brady, and R. N. Cohen
The Nuclear Receptor Corepressors NCoR and SMRT Decrease Peroxisome Proliferator-activated Receptor {gamma} Transcriptional Activity and Repress 3T3-L1 Adipogenesis
J. Biol. Chem., April 8, 2005; 280(14): 13600 - 13605.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
R. K. Semple, A. Meirhaeghe, A. J. Vidal-Puig, J. W. R. Schwabe, D. Wiggins, G. F. Gibbons, M. Gurnell, V. K. K. Chatterjee, and S. O'Rahilly
A Dominant Negative Human Peroxisome Proliferator-Activated Receptor (PPAR){alpha} Is a Constitutive Transcriptional Corepressor and Inhibits Signaling through All PPAR Isoforms
Endocrinology, April 1, 2005; 146(4): 1871 - 1882.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
K. L. Burnstein and C. W. Luetje
Hormone Resistance: It's SMRT to Fight Repression
Endocrinology, April 1, 2004; 145(4): 1525 - 1526.
[Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2003 by The Endocrine Society