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Ligand Modulated Antagonism of PPAR gamma by Genomic and Non-Genomic Actions of PPAR delta

Gustafsson, Mattias LU ; Palmer, Colin and Knight, Deborah (2009) In PLoS ONE 4(9).
Abstract
Abstract Top

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... (More)
Abstract Top

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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
4
issue
9
publisher
Public Library of Science
external identifiers
  • wos:000269970000013
  • scopus:70349492462
ISSN
1932-6203
DOI
10.1371/journal.pone.0007046
language
English
LU publication?
yes
id
85429e72-1168-40b6-a769-dcca9df36919 (old id 1474335)
alternative location
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007046
date added to LUP
2010-01-28 09:38:09
date last changed
2017-08-13 03:53:38
@article{85429e72-1168-40b6-a769-dcca9df36919,
  abstract     = {Abstract Top<br/><br>
Background<br/><br>
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.<br/><br>
<br/><br>
Methodology/Principal Findings<br/><br>
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.<br/><br>
<br/><br>
Conclusions/Significance<br/><br>
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.},
  articleno    = {e7046},
  author       = {Gustafsson, Mattias and Palmer, Colin and Knight, Deborah},
  issn         = {1932-6203},
  language     = {eng},
  number       = {9},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Ligand Modulated Antagonism of PPAR gamma by Genomic and Non-Genomic Actions of PPAR delta},
  url          = {http://dx.doi.org/10.1371/journal.pone.0007046},
  volume       = {4},
  year         = {2009},
}