Antagonism of COUP-TF and PPAR alpha/RXR alpha on the activation of the malic enzyme gene promoter: modulation by 9-cis RA.
We previously demonstrated that heterodimers of the Peroxisome Proliferator Activated Receptor alpha (PPAR alpha) and the Retinoid X Receptor alpha (RXR alpha) stimulate malic enzyme gene transcription through a regulatory element in the promoter region (ME-PPRE). In this report, we show that the orphan nuclear receptor COUP-TF also displays affinity for the ME-PPRE and competes with PPAR alpha/RXR alpha for binding to this element. In transient transfections of a reporter driven by the MRE-PPRE in a heterologous or in the homologous promoter context, COUP-TF strongly antagonizes the transactivation by PPAR alpha RXR alpha in the absence of exogenously added ligands. Although 9-cis RA did not further enhance the transcriptional effects of the heterodimers activated by ciprofibrate, it greatly impaired the suppressive effects of COUP-TF on the ciprofibrate activated PPAR alpha/RXR alpha. We conclude that the antagonism by COUP-TF uncovers differential activation states of PPAR alpha/RXR alpha heterodimers in the absence and in the presence of 9-cis RA.
Baes
M
M
Laboratory for Clinical Chemistry, Catholic University of Leuven, Faculty of Pharmaceutical Sciences, Onderwijs en Navorsing, Belgium.
Castelein
H
H
Desmet
L
L
Declercq
P E
PE
D000818:Animals; D001667:Binding, Competitive; D051838:COUP Transcription Factor I; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D046911:Macromolecular Substances; D008291:Malate Dehydrogenase / Q000235:genetics*; D051379:Mice; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D011965:Receptors, Glucocorticoid; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*
D051838:COUP Transcription Factor I; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; C497590:Nr2f1 protein, mouse; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D008291:Malate Dehydrogenase; C030574:malate dehydrogenase (decarboxylating)