Ligand Modulated Antagonism of PPAR gamma by Genomic and Non-Genomic Actions of PPAR delta
(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:
https://lup.lub.lu.se/record/1474335
- author
- Gustafsson, Mattias LU ; Palmer, Colin and Knight, Deborah
- organization
- publishing date
- 2009
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS ONE
- volume
- 4
- issue
- 9
- article number
- e7046
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000269970000013
- scopus:70349492462
- pmid:19756148
- 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
- 2016-04-01 13:16:11
- date last changed
- 2022-03-13 23:07:43
@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.}},
author = {{Gustafsson, Mattias and Palmer, Colin and Knight, Deborah}},
issn = {{1932-6203}},
language = {{eng}},
number = {{9}},
publisher = {{Public Library of Science (PLoS)}},
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}},
doi = {{10.1371/journal.pone.0007046}},
volume = {{4}},
year = {{2009}},
}