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Cell Growth & Differentiation Vol. 11, 447-454, August 2000
© 2000 American Association for Cancer Research

8S-Lipoxygenase Products Activate Peroxisome Proliferator-activated Receptor {alpha} and Induce Differentiation in Murine Keratinocytes1

Stephanie J. Muga2, Philippe Thuillier2, Amy Pavone, Joyce E. Rundhaug, William E. Boeglin, Mitsuo Jisaka, Alan R. Brash and Susan M. Fischer3

University of Texas, M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957 [S. J. M., P. T., A. P., J. E. R., S. M. F.]; Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602 [W. E. B., M. J., A. R. B.]

To determine the function and mechanism of action of the 8S-lipoxygenase (8-LOX) product of arachidonic acid, 8S-hydroxyeicosatetraenoic acid (8S-HETE), which is normally synthesized only after irritation of the epidermis, transgenic mice with 8-LOX targeted to keratinocytes through the use of a loricrin promoter were generated. Histological analyses showed that the skin, tongue, and stomach of transgenic mice are highly differentiated, and immunoblotting and immunohistochemistries of skin showed higher levels of keratin-1 expression compared with wild-type mice. The labeling index, however, of the transgenic epidermis was twice that of the wild-type epidermis. Furthermore, 8S-HETE treatment of wild-type primary keratinocytes induced keratin-1 expression. Peroxisome proliferator activated receptor {alpha} (PPAR{alpha}) was identified as a crucial component of keratin-1 induction through transient transfection with expression vectors for PPAR{alpha}, PPAR{gamma}, and a dominant-negative PPAR, as well as through the use of known PPAR agonists. From these studies, it is concluded that 8S-HETE plays an important role in keratinocyte differentiation and that at least some of its effects are mediated by PPAR{alpha}.




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Copyright © 2000 by the American Association of Cancer Research.