Peroxisome proliferator-activated receptor response specificities as defined in yeast and mammalian cell transcription assays.
Peroxisome proliferators include a heterogeneous group of xenobiotic agents 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 peroxisome proliferator-activated receptors (PPAR). Recently it has been shown that DNA binding of PPAR is contingent upon heterodimerization with a member of the retinoic acid X (RXR) family of receptors. In this report transcription parameters of a rat PPAR alpha were analyzed using mammalian and yeast cotransfection assays. PPAR activity was observed to be peroxisome proliferator dependent in the mammalian cotransfection assay, and heterodimer dependent but peroxisome proliferator independent in a yeast version of the same assay. Moreover, when the naturally 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 mammalian cell assay. Finally, the combination of peroxisome proliferator and 9-cis-RA had very little added effect on the yeast cell assay but again produced a cell-specific synergistic response in the mammalian cell assay. These data demonstrate that PPAR transcriptional activity is strongly influenced by the RXR family of receptors, and that peroxisome proliferators may be regulating PPAR mammalian cell activity through a secondary mechanism.
Henry
K
K
Department of Biochemistry, University of Kentucky, Lexington 40536-0084, USA.
O'Brien
M L
ML
Clevenger
W
W
Jow
L
L
Noonan
D J
DJ
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D008969:Molecular Sequence Data; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis* / Q000737:chemistry / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D047488:Retinoid X Receptors; D012260:Ribonucleases / Q000032:analysis; D012441:Saccharomyces cerevisiae / Q000737:chemistry*; D014157:Transcription Factors / Q000032:analysis* / Q000737:chemistry / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics*; D014162:Transfection / Q000235:genetics
D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D012260:Ribonucleases