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An Upstream Region of the Enoyl-Coenzyme A Hydratase/3-Hydroxyacyl-Coenzyme A Dehydrogenase Gene Directs Luciferase Expression in Liver in Response to Peroxisome Proliferators in Transgenic Mice¹

Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611 [K. A., C-Y. F., S. S. D., A. V. Y., P. M. I., M. S. R., J. K. R.]; Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5 Canada [R. A. R., J. P. C.]; and Department of Biology, University of California San Diego, La Jolla, California 92093 [S. S.]

Peroxisome proliferators, which are structurally diverse nonmutagenic agents, induce hepatocarcinogenesis in rats and mice. Exposure to these xenobiotics leads to a rapid and coordinated transcriptional activation of the genes for the peroxisomal ß-oxidation enzyme system pathway in the liver. We have previously identified a peroxisome proliferator-responsive element in the 5'-flanking region of the rat peroxisomal hydratase/dehydrogenase (PBE) gene, the second enzyme in the ß-oxidation pathway. The peroxisome proliferator-responsive element in the PBE gene was shown to direct the induction of a luciferase reporter gene in vitro. We have now used this 3.2-kilobase 5'-flanking region of the PBE gene fused to the coding region of luciferase to generate transgenic mice. Three independent lines of transgenic mice expressed luciferase in response to ciprofibrate, a peroxisome proliferator. The induction of luciferase is specific to the liver; this agrees with the tissue-specific induction of PBE. Two other hypolipidemic drugs, nafenopin and Wy-14,643, were also capable of inducing luciferase activity in the liver. This study suggests that the PBE upstream element can be used to direct and modulate the expression of cloned genes by changing the levels of peroxisome proliferators. Also, the PBE-luciferase transgenic mouse should be an excellent model system for screening xenobiotics for potential peroxisome proliferator property.

¹ This work was supported by NIH Grant R37 GM23750, a Veterans Administration Research Advisory Grant, and the Joseph L. Mayberry, Sr. Endowment Research Fund.

² To whom requests for reprints should be addressed, at Northwestern University Medical School, Department of Pathology, Ward Building 6-204, 303 E. Chicago Avenue, Chicago, IL 60611-3008.

Received 1/10/94. Accepted 3/18/94.

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