SUBTYPE-DEPENDENT AND RESPONSE ELEMENT-DEPENDENT DIFFERENCES IN TRANSACTIVATION BY PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA AND RECEPTOR-GAMMA

Peroxisome proliferator-activated receptors (PPAR) modulate transcript ion by binding to specific peroxisome proliferator-response elements ( PPRE) through heterodimerization with the 9-cis retinoic acid receptor (RXR). To investigate potential subtype and response element-dependen t differences in transcriptional activation by PPARs, we expressed PPA R alpha or PPAR gamma 2, along with RXR alpha, in the yeast Saccharoro myces cerevisiae and compared their ability to activate transcription of reporter genes containing a PPRE from either the rat acyl-CoA oxida se (AOx) or hydratase-dehydrogenase (HD) gene. PPAR gamma 2 and RXR al pha, when coexpressed from low copy vectors, potently and synergistica lly activated transcription of the AOx-PPRE reporter gene, but only we akly stimulated transcription of the HD-PPRE reporter gene. This respo nse element preference, which was also observed in mammalian cells, co uld not be attributed to differences in binding affinity of PPAR gamma 2/RXR alpha heterodimers to these elements in vitro. Interestingly, P PAR gamma 2 expressed from a high copy vector was able to strongly act ivate transcription of the HD-PPRE reporter gene, even in the absence of coexpressed RXR alpha. In comparison to the findings with PPAR gamm a 2, the HD-PPRE served as a significantly more robust response elemen t for PPAR alpha as compared to the AOx-PPRE. PPRE-dependent transcrip tional activation by PPAR alpha correlated with binding efficiencies o f PPAR alpha/RXR alpha to the response element. Our findings demonstra te that the transactivation potential of PPAR subtypes can be differen tially modulated by distinct PPREs. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.