Tyrosine Agonists Reverse the Molecular Defects Associated with Dominant-Negative Mutations in Human Peroxisome Proliferator-Activated Receptor γ

Agostini, Maura; Gurnell, Mark; Savage, David B.; Wood, Emily M.; Smith, Aaron G.; Rajanayagam, Odelia; Garnes, Keith T.; Levinson, Sidney H.; Xu, H. Eric; Schwabe, John W. R.; Willson, Timothy M.; O’Rahilly, Stephen; Chatterjee, Krishna

doi:10.1210/en.2003-1271

Cited by 58 publications

(52 citation statements)

References 39 publications

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“…A number of diseases are associated with mutations in NR genes, frequently affecting the LBD (57,58). In some cases, the functional defect can be (partially) rescued by specific ligands as exemplified by the effects of synthetic tyrosinebased agonists on the FPLD3-associated PPAR␥ V318M and P495L mutants (59). Characterization of NR mutants using NR-coregulator interaction profiling can therefore provide the rationale for therapy in such cases.…”

Section: Figmentioning

confidence: 99%

Nuclear Receptor-Coregulator Interaction Profiling Identifies TRIP3 as a Novel Peroxisome Proliferator-activated Receptor γ Cofactor

Koppen

Houtman

Pijnenburg

et al. 2009

Molecular & Cellular Proteomics

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Nuclear receptors (NRs) are major targets for drug discovery and have key roles in development and homeostasis as well as in many diseases such as obesity, diabetes, and cancer. NRs are ligand-dependent transcription factors that need to work in concert with so-called transcriptional coregulators, including corepressors and coactivators, to regulate transcription. Upon ligand binding, NRs undergo a conformational change, which alters their binding preference for coregulators. Short ␣-helical sequences in the coregulator proteins, LXXLL (in coactivators) or LXXXIXXXL (in corepressors), are essential for the NR-coregulator interactions. However, little is known on how specificity is dictated. To obtain a comprehensive overview of NR-coregulator interactions, we used a microarray approach based on interactions between NRs and peptides derived from known coregulators. Using the peroxisome proliferator-activated receptor ␥ (PPAR␥) as a model NR, we were able to generate ligand-specific interaction profiles (agonist rosiglitazone versus antagonist GW9662 versus selective PPAR␥ modulator telmisartan) and characterize NR mutants and isotypes (PPAR␣, -␤/␦, and -␥). Importantly, based on the NR-coregulator interaction profile, we were able to identify TRIP3 as a novel regulator of PPAR␥-mediated adipocyte differentiation. These findings indicate that NR-coregulator interaction profiling may be a useful tool for drug development and biological discovery. Molecular & Cellular Proteomics 8:2212-2226, 2009. Nuclear receptors (NRs)1 are ligand-inducible transcription factors involved in development and homeostasis that play key roles in many diseases, including diabetes, cancer, and obesity (1). NRs consist of several functional domains, which exhibit varying degrees of conservation among members of the receptor family. The poorly conserved N terminus contains the activation function 1 (AF-1) domain, the activity of which is often regulated by post-translational modifications. Centrally located is the DNA binding domain, which is highly conserved among species and between nuclear receptors. The ligand binding domain (LBD), which is also relatively well conserved in terms of primary amino acid sequence, mediates ligand binding, and contains the powerful ligand-dependent activation function (AF-2). LBD crystal structures have revealed a canonical fold consisting of 13 ␣-helices and a small four-stranded ␤-sheet (2). Upon ligand binding, the AF-2 helix (also referred to as helix 12) is stabilized in an active state (3). Depending on the conformation of the LBD and its modulation by ligand, NRs can recruit or release transcriptional coregulator proteins that perform all of the subsequent reactions needed to induce or repress transcription of target genes (4). Coregulators are often components of large multiprotein complexes that act in a sequential and/or combinatorial fashion to modify chromatin and to recruit basal transcription factors and RNA polymerase II (5). In general, the transcriptional coregulator family consists of coa...

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Section: Figmentioning

confidence: 99%

Nuclear Receptor-Coregulator Interaction Profiling Identifies TRIP3 as a Novel Peroxisome Proliferator-activated Receptor γ Cofactor

Koppen

Houtman

Pijnenburg

et al. 2009

Molecular & Cellular Proteomics

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“…In vitro studies of both mutations suggest a destabilization of the PPARg configuration more favorable for receptor-corepressor interactions with dominant-negative properties. Interestingly, a PPARg ligand stabilizes the receptor structure in the active conformation and promotes co-repressor release, which most likely explains the improvement of these patients' condition after TZD treatment [192].…”

Section: Pparg Loss Of Function Mutationsmentioning

confidence: 99%

Fat poetry: a kingdom for PPARγ

2007

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Adipose tissue is not an inert cell mass contributing only to the storage of fat, but a sophisticated ensemble of cellular components with highly specialized and complex functions. In addition to managing the most important energy reserve of the body, it secretes a multitude of soluble proteins called adipokines, which have beneficial or, alternatively, deleterious effects on the homeostasis of the whole body. The expression of these adipokines is an integrated response to various signals received from many organs, which depends heavily on the integrity and physiological status of the adipose tissue. One of the main regulators of gene expression in fat is the transcription factor peroxisome proliferatoractivated receptor g (PPARg), which is a fatty acid-and eicosanoid-dependent nuclear receptor that plays key roles in the development and maintenance of the adipose tissue. Furthermore, synthetic PPARg agonists are therapeutic agents used in the treatment of type 2 diabetes.This review discusses recent knowledge on the link between fat physiology and metabolic diseases, and the roles of PPARg in this interplay via the regulation of lipid and glucose metabolism. Finally, we assess the putative benefits of targeting this nuclear receptor with still-to-be-identified highly selective PPARg modulators.

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“…In 293EBNA cells without the addition of an exogenous ligand, PPARG did not exhibit silencing function but rather constitutive activation of basal transcription (Barroso et al 1999, Agostini et al 2004, Semple et al 2006. Additionally, overexpression of NCoR did not potentiate the suppression by PPARG2 of acyl-CoA oxidase-derived PPRE (Aox-PPRE) in 293T cells (Zamir et al 1997).…”

Section: Introductionmentioning

confidence: 95%

“…Barroso et al (1999) and Savage et al (2003) reported two different heterozygous mutations, PPARG1-P467L and V290M, in patients with severe insulin resistance. Both mutants, PPARG1-P467L in particular, have very low affinity for the PPARG ligands and constitutively bind with CoR (Barroso et al 1999, Agostini et al 2004. They are believed to be resistant to the endogenous ligand since they exhibited no transactivation in 293EBNA cells in the absence of an exogenous ligand (Barroso et al 1999, Agostini et al 2004.…”

Section: Introductionmentioning

confidence: 99%

“…Both mutants, PPARG1-P467L in particular, have very low affinity for the PPARG ligands and constitutively bind with CoR (Barroso et al 1999, Agostini et al 2004. They are believed to be resistant to the endogenous ligand since they exhibited no transactivation in 293EBNA cells in the absence of an exogenous ligand (Barroso et al 1999, Agostini et al 2004. These mutant PPARG1s also exhibited potent dominant negative effects (DNEs) on the ligand-induced transactivation by wild-type PPARG1 (Barroso et al 1999).…”

Section: Introductionmentioning

confidence: 99%

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The role of the amino-terminal domain in the interaction of unliganded peroxisome proliferator-activated receptor γ-2 with nuclear receptor co-repressor

Suzuki¹,

Sasaki²,

Morita³

et al. 2010

Journal of Molecular Endocrinology

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Peroxisome proliferator-activated receptor g-2 (PPARG2) is a ligand-dependent transcriptional factor involved in the pathogenesis of insulin resistance. In the presence of a ligand, PPARG2 associates with co-activators, while it recruits co-repressors (CoRs) in the absence of a ligand. It has been reported that the interaction of liganded PPARG2 with co-activators is regulated by the amino-terminal A/B domain (NTD) via inter-domain communication. However, the role of the NTD is unknown in the case of the interaction between unliganded PPARG2 and CoRs. To elucidate this, total elimination of the influence of ligands is required, but the endogenous ligands of PPARG2 have not been fully defined. PPARG1-P467L, a naturally occurring mutant of PPARG1, was identified in a patient with severe insulin resistance. Reflecting its very low affinity for various ligands, this mutant does not have transcriptional activity in the PPAR response element, but exhibits dominant negative effects (DNEs) on liganded wild-type PPARG2-mediated transactivation. Using the corresponding PPARG2 mutant, PPARG2-P495L, we evaluated the role of the NTD in the interaction between unliganded PPARG2 and CoRs. Interestingly, the DNE of PPARG2-P495L was increased by the truncation of its NTD. NTD deletion also enhanced the DNE of a chimeric receptor, PT, in which the ligand-binding domain of PPARG2 was replaced with that of thyroid hormone receptor b-1. Moreover, NTD deletion facilitated the in vitro binding of nuclear receptor CoR with wild-type PPARG2, mutant P495L, and the PT chimera (PPARG2-THRB). Inter-domain communication in PPARG2 regulates not only ligand-dependent transactivation but also ligand-independent silencing.

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Tyrosine Agonists Reverse the Molecular Defects Associated with Dominant-Negative Mutations in Human Peroxisome Proliferator-Activated Receptor γ

Cited by 58 publications

References 39 publications

Nuclear Receptor-Coregulator Interaction Profiling Identifies TRIP3 as a Novel Peroxisome Proliferator-activated Receptor γ Cofactor

Nuclear Receptor-Coregulator Interaction Profiling Identifies TRIP3 as a Novel Peroxisome Proliferator-activated Receptor γ Cofactor

Fat poetry: a kingdom for PPARγ

The role of the amino-terminal domain in the interaction of unliganded peroxisome proliferator-activated receptor γ-2 with nuclear receptor co-repressor

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