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J. Biol. Chem., Vol. 278, Issue 37, 35184-35192, September 12, 2003

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Epoxyeicosatrienoic Acids Activate Transglutaminases in Situ and Induce Cornification of Epidermal Keratinocytes^*

Patricia A. Ladd , Liping Du , Jorge H. Capdevila  ¶ ||, Raymond Mernaugh  and Diane S. Keeney   ** 

From the ^**Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37212 and the Departments of Medicine (Divisions of Dermatology and ^¶Nephrology) and Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

The cytochrome P450 CYP2B19 is a keratinocyte-specific arachidonic acid epoxygenase expressed in the granular cell layer of mouse epidermis. In cultured keratinocytes, CYP2B19 mRNAs are up-regulated coordinately with those of profilaggrin, another granular cell-specific marker. We investigated effects of the CYP2B19 metabolites 11,12- and 14,15-epoxyeicosatrienoic acids (EETs) on keratinocyte transglutaminase activities and cornified cell envelope formation. Keratinocytes were differentiated in vitro in the presence of biotinylated cadaverine. Transglutaminases cross-linked this substrate into endogenous proteins in situ; an enzyme-linked immunosorbent assay was used to quantify the biotinylated proteins. Exogenously added or endogenously formed 14,15-EET increased transglutaminase cross-linking activities in cultured human and mouse epidermal keratinocytes in a modified in situ assay. Transglutaminase activities increased 8-fold (p 0.02 versus mock control) in human keratinocytes transduced with adenovirus particles expressing a 14S,15R-EET epoxygenase (P450 BM3v). The physiological transglutaminase substrate involucrin was preferentially biotinylated in situ, determined by immunoblotting and mass spectrometry. P450 BM3v-induced transglutaminase activation was associated with increased 14,15-EET formation (p = 0.002) and spontaneous cell cornification (p 0.001). Preferential involucrin biotinylation and the increased cornified cell envelope formation provided evidence that transglutaminases mediated the P450 BM3v-induced cross-linking activities. These results support a physiological role for 14,15-EET epoxygenases in regulating epidermal cornification, and they have important implications for epidermal barrier functions in vivo.

Received for publication, February 17, 2003 , and in revised form, June 18, 2003.

^* This work was supported by National Institutes of Health (NIH) P30 Grants AR41943, ES00267, and CA68485. 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.

^|| Supported by NIH Grant GM37922.

Supported by the Department of Veterans Affairs and NIH Grant AR45603. To whom correspondence should be addressed: Dept. of Medicine/Dermatology & Biochemistry, Vanderbilt University, 607 Light Hall, Nashville, TN 37232-0146. Tel.: 615-327-4751 (ext. 5283); Fax: 615-322-4349; E-mail: diane.keeney{at}vanderbilt.edu.

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