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 Prolife rator Activated Receptor alpha (PPAR alpha) and the Retinoid X Recepto r 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 affini ty for the ME-PPRE and competes with PPAR alpha/RXR alpha for binding to this element. In transient transfections of a reporter driven by th e ME-PPRE in a heterologous or in the homologous promoter context, COU P-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 activ ated by ciprofibrate, it greatly impaired the suppressive effects of C OUP-TF on the ciprofibrate activated PPAR alpha/RXR alpha. We conclude that the antagonism by COUP-TF uncovers differential activation state s of PPAR alpha/RXR alpha heterodimers in the absence and in the prese nce of 9-cis RA. (C) 1995 Academic Press, Inc.