title: Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells.
abstract: In addition to its important functions in detoxification of foreign chemicals and biosynthesis of steroid hormones, the cytochrome P450 enzyme system metabolizes arachidonate to 14,15-epoxyeicosatrienoic acid (14,15-EET). This study demonstrates that a P450 arachidonate epoxygenase metabolite can activate cleavage of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and delineates an essential role for HB-EGF in the mitogenic effects of this lipid mediator. Blockade of HB-EGF processing or EGF receptor (EGFR) inhibited 14,15-EET-stimulated early mitogenic signals and DNA synthesis. 14,15-EET failed to induce mitogenesis in cell lines expressing minimal HB-EGF, whereas 14,15-EET induced soluble HB-EGF release into the conditioned media of cell lines that both express high levels of HB-EGF and display mitogenic response to this lipid mediator. Moreover, transfection of a bacterial 14,15-epoxygenase established intracellular endogenous 14,15-EET biosynthesis in cultured cell systems, which allowed direct confirmation of involvement of EGFR transactivation in the endogenous 14,15-EET-mediated mitogenic signaling pathway. This mechanism involves EET-dependent activation of metalloproteinases and release of the potent mitogenic EGFR ligand, HB-EGF.
authors: Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
authors: Jian-Kang
authors: JK
authors: Chen
authors: Jorge
authors: J
authors: Capdevila
authors: Raymond C
authors: RC
authors: Harris
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D003001:Cloning, Molecular; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008954:Models, Biological; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D015398:Signal Transduction; D013552:Swine; D013876:Thiophenes / Q000494:pharmacology; D015533:Transcriptional Activation; D020298:U937 Cells
chemical_list: C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D013876:Thiophenes; D010649:Phenylalanine; D004815:Epidermal Growth Factor; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C080985:batimastat; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2