cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor.
The human peroxisome proliferator activated receptor (hPPAR) was cloned from a human liver cDNA library. The cDNA exhibited 85% and 91% DNA and deduced amino acid sequence identity with mouse PPAR (mPPAR), respectively. The hPPAR gene was mapped on human chromosome 22 slightly telomeric to a linkage group of six genes and genetic markers that are located in the general region 22q12-q13.1. Cotransfection assays of mouse Hepa 1 cells were used to roughly compare the ability of hPPAR- and mPPAR-expressed cDNAs to trans-activate the acyl CoA oxidase (ACO) PPAR response element located 5' upstream to the minimal thymidine kinase promoter driving the expression of the chloramphenicol acetyl transferase (CAT) reporter gene. Both receptors elicited a response with the prototypical peroxisome proliferators nafenopin, clofibrate, and WY-14,643. Moreover, using cotransfection assays in which the CAT reporter plasmid contained the CYP4 A6 gene response element rather than the ACO element, it was shown that hPPAR is capable of very efficiently trans-activating a second PPAR response element. These results indicate that the PPAR is present in humans in a form that is functional and can trans-activate response elements derived from two different genes, the rat ACO and the rabbit CYP4A6.
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Laboratory of Molecular Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892.
Yi
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HF
McBride
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Gonzalez
F J
FJ
D042962:Acyl-CoA Oxidase; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping; D002892:Chromosomes, Human, Pair 22; D002994:Clofibrate / Q000494:pharmacology; D003001:Cloning, Molecular; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004247:DNA / Q000235:genetics*; D019003:Deoxyribonuclease HpaII; D015252:Deoxyribonucleases, Type II Site-Specific; D015723:Gene Library; D008040:Genetic Linkage; D006801:Humans; D008126:Lod Score; D051379:Mice; D008830:Microbodies / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006899:Mixed Function Oxygenases / Q000235:genetics; D008969:Molecular Sequence Data; D009255:Nafenopin / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides; D010088:Oxidoreductases / Q000235:genetics; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear; D013937:Thymidine Kinase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D009838:Oligodeoxyribonucleotides; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D009255:Nafenopin; C006253:pirinixic acid; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D042926:Cytochrome P-450 CYP4A; D042962:Acyl-CoA Oxidase; D015500:Chloramphenicol O-Acetyltransferase; D013937:Thymidine Kinase; D019003:Deoxyribonuclease HpaII; D015252:Deoxyribonucleases, Type II Site-Specific; C027046:TCGA-specific type II deoxyribonucleases; D002994:Clofibrate