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FP Prostanoid Receptor-Mediated Induction of the Expression of Early Growth Response Factor-1 by Activation of a Ras/Raf/Mitogen-Activated Protein Kinase Signaling Cascade

Department of Pharmacology and Toxicology, College of Pharmacy, the University of Arizona, Tucson, Arizona (W.X., C.L.C., J.W.R.); Department of Medical Pharmacol, College of Medicine, the University of Arizona, Tucson, Arizona (H.S., Q.M.C.); and Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (H.F.)

FP prostanoid receptors are G-protein-coupled receptors whose physiological activator is prostaglandin-F₂ (PGF₂). PGF₂ has been implicated in wound healing and cardiac hypertrophy, which are both known to involve the induction of the immediate-early response gene, early growth response factor-1 (EGR-1). We hypothesized that activation of the human FP receptor by PGF₂ could induce the expression of EGR-1 and found that 1 µM PGF₂ produced a time-dependent induction of both mRNA and protein expression for EGR-1. This FP receptor-mediated induction of EGR-1 expression involved activation of the small GTPase Ras followed by activation of C-Raf and the mitogen-activated protein (MAP) kinase kinases 1 and 2 (MEK1/2). Thus, induction of EGR-1 expression by PGF₂ was blocked using dominant-negative constructs of Ras and C-Raf and the Raf kinase inhibitor 4-(4-(3-(4-chloro-3-trifluoromethylphenyl)ureido)phenoxy)-pyridine-2-carboxyllic acid methyamide-4-methylbenzenesulfonate (BAY43-9006). Likewise, the MEK1/2 inhibitor 2'-amino-3'-methoxyflavone (PD98059) blocked the induction of EGR-1 expression by PGF₂. FP receptor stimulation by PGF₂ induced the phosphorylation of C-Raf, MEK1/2, and extracellular signal-regulated kinases 1 and 2, consistent with the activation of a MAP kinase signaling cascade. PGF₂ was also found to induce the expression of EGR-1 in rat cardiomyocytes through the activation of endogenous FP receptors. This induction of EGR-1 expression in cardiomyocytes also involved the activation of Raf and MAP kinase signaling and was dependent on the activation of protein kinase C. This is the first report to show the regulation of EGR-1 expression after PGF₂ activation of FP receptors and suggests that this could be an early event involved in wound healing and cardiac hypertrophy.

Address correspondence to: Dr. John W. Regan, Department of Pharmacology and Toxicology, College of Pharmacy/The University of Arizona, 1703 E. Mabel St., Tucson, AZ 85721-0207. E-mail: regan{at}pharmacy.arizona.edu