PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR RESPONSE SPECIFICITIES AS DEFINED IN YEAST AND MAMMALIAN-CELL TRANSCRIPTION ASSAYS

Peroxisome proliferators include a heterogeneous group of xenobiotic a gents capable of inducing peroxisome proliferation and hepatocellular carcinomas in rodent model systems. These chemicals appear to mediate their activity through a family of transcription factors known as pero xisome proliferator-activated receptors (PPAR). Recently it has been s hown that DNA binding of PPAR is contingent upon heterodimerization wi th a member of the retinoic acid X (RXR) family of receptors. In this report transcription parameters of a rat PPAR alpha were analyzed usin g mammalian and yeast cotransfection assays. PPAR activity was observe d to be peroxisome proliferator dependent in the mammalian cotransfect ion assay, and heterodimer dependent but peroxisome proliferator indep endent in a yeast version of the same assay. Moreover, when the natura lly occurring ligand for RXR, 9-cis-retinoic acid (RA), was tested in the same assays, it was observed to generate an RXR-specific response in the yeast cell assay but host cell-specific response in the mammali an cell assay. Finally, the combination of peroxisome proliferator and 9-cis-RA had very little added effect on the yeast cell assay but aga in produced a cell-specific synergistic response in the mammalian cell assay. These data demonstrate that PPAR transcriptional activity is s trongly influenced by the RXR family of receptors, and that peroxisome proliferators may be regulating PPAR mammalian cell activity through a secondary mechanism. (C) 1995 Academic Press, Inc.