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Ligand Modulated Antagonism of PPARγ by Genomic and Non-Genomic Actions of PPARδ

BACKGROUND: Members of the Peroxisome Proliferator Activated Receptor, PPAR, subfamily of nuclear receptors display complex opposing and overlapping functions and a wide range of pharmacological and molecular genetic tools have been used to dissect their specific functions. Non-agonist bound PPARδ h...

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Detalles Bibliográficos
Autores principales: Gustafsson, Mattias C. U., Knight, Deborah, Palmer, Colin N. A.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737640/
https://www.ncbi.nlm.nih.gov/pubmed/19756148
http://dx.doi.org/10.1371/journal.pone.0007046
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author Gustafsson, Mattias C. U.
Knight, Deborah
Palmer, Colin N. A.
author_facet Gustafsson, Mattias C. U.
Knight, Deborah
Palmer, Colin N. A.
author_sort Gustafsson, Mattias C. U.
collection PubMed
description BACKGROUND: Members of the Peroxisome Proliferator Activated Receptor, PPAR, subfamily of nuclear receptors display complex opposing and overlapping functions and a wide range of pharmacological and molecular genetic tools have been used to dissect their specific functions. Non-agonist bound PPARδ has been shown to repress PPAR Response Element, PPRE, signalling and several lines of evidence point to the importance of PPARδ repressive actions in both cardiovascular and cancer biology. METHODOLOGY/PRINCIPAL FINDINGS: In this report we have employed transient transfections and luciferase reporter gene technology to study the repressing effects of PPARδ and two derivatives thereof. We demonstrate for the first time that the classical dominant negative deletion of the Activation Function 2, AF2, domain of PPARδ show enhanced repression of PPRE signalling in the presence of a PPARδ agonist. We propose that the mechanism for the phenomenon is increased RXR heterodimerisation and DNA binding upon ligand binding concomitant with transcriptional co-repressor binding. We also demonstrated ligand-dependent dominant negative action of a DNA non-binding derivative of PPARδ on PPARγ1 signalling. This activity was abolished upon over-expression of RXRα suggesting a role for PPAR/cofactor competition in the absence of DNA binding. CONCLUSIONS/SIGNIFICANCE: These findings are important in understanding the wide spectrum of molecular interactions in which PPARδ and PPARγ have opposing biological roles and suggest novel paradigms for the design of different functional classes of nuclear receptor antagonist drugs.
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spelling pubmed-27376402009-09-16 Ligand Modulated Antagonism of PPARγ by Genomic and Non-Genomic Actions of PPARδ Gustafsson, Mattias C. U. Knight, Deborah Palmer, Colin N. A. PLoS One Research Article BACKGROUND: Members of the Peroxisome Proliferator Activated Receptor, PPAR, subfamily of nuclear receptors display complex opposing and overlapping functions and a wide range of pharmacological and molecular genetic tools have been used to dissect their specific functions. Non-agonist bound PPARδ has been shown to repress PPAR Response Element, PPRE, signalling and several lines of evidence point to the importance of PPARδ repressive actions in both cardiovascular and cancer biology. METHODOLOGY/PRINCIPAL FINDINGS: In this report we have employed transient transfections and luciferase reporter gene technology to study the repressing effects of PPARδ and two derivatives thereof. We demonstrate for the first time that the classical dominant negative deletion of the Activation Function 2, AF2, domain of PPARδ show enhanced repression of PPRE signalling in the presence of a PPARδ agonist. We propose that the mechanism for the phenomenon is increased RXR heterodimerisation and DNA binding upon ligand binding concomitant with transcriptional co-repressor binding. We also demonstrated ligand-dependent dominant negative action of a DNA non-binding derivative of PPARδ on PPARγ1 signalling. This activity was abolished upon over-expression of RXRα suggesting a role for PPAR/cofactor competition in the absence of DNA binding. CONCLUSIONS/SIGNIFICANCE: These findings are important in understanding the wide spectrum of molecular interactions in which PPARδ and PPARγ have opposing biological roles and suggest novel paradigms for the design of different functional classes of nuclear receptor antagonist drugs. Public Library of Science 2009-09-16 /pmc/articles/PMC2737640/ /pubmed/19756148 http://dx.doi.org/10.1371/journal.pone.0007046 Text en Gustafsson et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Gustafsson, Mattias C. U.
Knight, Deborah
Palmer, Colin N. A.
Ligand Modulated Antagonism of PPARγ by Genomic and Non-Genomic Actions of PPARδ
title Ligand Modulated Antagonism of PPARγ by Genomic and Non-Genomic Actions of PPARδ
title_full Ligand Modulated Antagonism of PPARγ by Genomic and Non-Genomic Actions of PPARδ
title_fullStr Ligand Modulated Antagonism of PPARγ by Genomic and Non-Genomic Actions of PPARδ
title_full_unstemmed Ligand Modulated Antagonism of PPARγ by Genomic and Non-Genomic Actions of PPARδ
title_short Ligand Modulated Antagonism of PPARγ by Genomic and Non-Genomic Actions of PPARδ
title_sort ligand modulated antagonism of pparγ by genomic and non-genomic actions of pparδ
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737640/
https://www.ncbi.nlm.nih.gov/pubmed/19756148
http://dx.doi.org/10.1371/journal.pone.0007046
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