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J. Biol. Chem., Vol. 282, Issue 2, 1498-1506, January 12, 2007

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Targeted Cyclooxygenase Gene (Ptgs) Exchange Reveals Discriminant Isoform Functionality^*

Ying Yu, Jinjin Fan, Yiqun Hui, Carol A. Rouzer, Lawrence J. Marnett, Andres J. Klein-Szanto^¶, Garret A. FitzGerald¹, and Colin D. Funk^||2

From the Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, the Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, the ^¶Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, and the ^||Departments of Biochemistry and Physiology, Queen's University, Kingston, Ontario K7L 3N6, Canada

The prostaglandin G/H synthase enzymes, commonly termed COX-1 and COX-2, differ markedly in their responses to regulatory stimuli and their tissue expression patterns. COX-1 is the dominant source of "housekeeping" prostaglandins, whereas COX-2 synthesizes prostaglandins of relevance to pain, inflammation, and mitogenesis. Despite these distinctions, the two enzymes are remarkably conserved, and their subcellular distributions overlap considerably. To address the functional interchangeability of the two isozymes, mice in which COX-1 is expressed under COX-2 regulatory elements were created by a gene targeting "knock-in" strategy. In macrophages from these mice, COX-1 was shown to be lipopolysaccharide-inducible in a manner analogous to COX-2 in wild-type macrophages. However, COX-1 failed to substitute effectively for COX-2 in lipopolysaccharide-induced prostaglandin E₂ synthesis at low concentrations of substrate and in the metabolism of the endocannabinoid 2-arachidonylglycerol. The marked depression of the major urinary metabolite of prostacyclin in COX-2 null mice was only partially rescued by COX-1 knock-in, whereas the main urinary metabolite of prostaglandin E₂ was rescued totally. Replacement with COX-1 partially rescued the impact of COX-2 deletion on reproductive function. The renal pathology consequent to COX-2 deletion was delayed but not prevented, whereas the corresponding peritonitis was unaltered. Insertion of COX-1 under the regulatory sequences that drive COX-2 expression indicated that COX-1 can substitute for some COX-2 actions and rescue only some of the consequences of gene disruption. Manipulation of COX-2 also revealed a preference for coupling with distinct downstream prostaglandin synthases in vivo. These mice will provide a valuable reagent with which to elucidate the distinct roles of the COX enzymes in mammalian biology.

Received for publication, October 23, 2006 , and in revised form, November 14, 2006.

^* This work was supported by Grants GM063130, HL62250, and GM15431 from the National Institutes of Health, Canadian Institutes of Health Research Grant MOP-79459, and American Heart Association National Scientist Development Grant 0730314N. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The Elmer Bobst Professor of Pharmacology.

² Holds a Tier I Canada Research Chair in Molecular, Cellular, and Physiological Medicine and is a Career Investigator of the Heart and Stroke Foundation of Canada. To whom correspondence should be addressed: Dept. of Physiology, Botterell Hall, Rm. 433 Queen's University, Kingston, Ontario K7L 3N6, Canada. Tel.: 613-533-3242; Fax: 613-533-6880; E-mail: funkc{at}post.queensu.ca.

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