Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells.

Chen JK, Capdevila J, Harris RC
Proc Natl Acad Sci U S A. 2002 99 (9): 6029-34

PMID: 11983897 · PMCID: PMC122896 · DOI:10.1073/pnas.092671899

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.

MeSH Terms (24)

Animals Cell Line Cloning, Molecular COS Cells Cytochrome P-450 Enzyme System DNA Epidermal Growth Factor Epithelial Cells Heparin-binding EGF-like Growth Factor Humans Intercellular Signaling Peptides and Proteins Ligands Models, Biological Muscle, Smooth Oxygenases Phenylalanine Phosphorylation Precipitin Tests Protein Binding Signal Transduction Swine Thiophenes Transcriptional Activation U937 Cells

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