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Contribution of Phospholipase D in Endothelin-1-Mediated Extracellular Signal-Regulated Kinase Activation and Proliferation in Rat Uterine Leiomyoma Cells¹

Laboratoire de signalisation et régulations cellulaires, IBBMC, CNRS UMR 8619, Bat 430 Université Paris Sud, 91 405 Orsay Cedex, France

Endothelin (ET)-1 is a mitogenic factor in numerous cell types, including rat myometrial cells. In the present study, we investigated the potential role of ET-1 in the proliferation of tumoral uterine smooth muscle cells (ELT-3 cells). We found that ET-1 exerted a more potent mitogenic effect in ELT-3 cells than in normal myometrial cells, as indicated by the increase in [³H]thymidine incorporation, cell number, and bromodeoxyuridine incorporation. The ET-1 was more efficient than platelet-derived growth factor and epidermal growth factor to stimulate proliferation. The ET-1-mediated cell proliferation was inhibited in the presence of U0126, a specific inhibitor of (mitogen-activated protein kinase ERK kinase), indicating that extracellular signal-regulated kinase (ERK) activation is involved. Additionally, ET-1 induced the activation of phospholipase (PL) D, leading to the synthesis of phosphatidic acid (PA). The ET-1-induced activation of PLD was twofold higher in ELT-3 cells compared to that in normal cells. The two cell types expressed mRNA for PLD1a and PLD2, whereas PLD1b was expressed only in ELT-3 cells. The exposure of cells to butan-1-ol reduced ET-1-mediated production of PA by PLD and partially inhibited ERK activation and DNA synthesis. Addition of exogenous PLD or PA in the medium reproduced the effect of ET-1 on ERK activation and cell proliferation. Collectively, these data indicate that ET-1 is a potent mitogenic factor in ELT-3 cells via a signaling pathway involving a PLD-dependent activation of ERK. This highlights the potential role of ET-1 in the development of uterine leiomyoma, and it reinforces the role of PLD in tumor growth.

¹ Supported by grants from the Centre National de la Recherche Scientifique and Université Paris Sud.

² Correspondence: Zahra Tanfin, CNRS UMR 8619, Bat 430 Université Paris Sud, 91 405 Orsay Cedex, France. FAX: 33 16 985 3715; zahra.tanfin{at}erc.u-psud.fr

This article has been cited by other articles:

				E. Billon-Denis, Z. Tanfin, and P. Robin Role of lysophosphatidic acid in the regulation of uterine leiomyoma cell proliferation by phospholipase D and autotaxin J. Lipid Res., February 1, 2008; 49(2): 295 - 307. [Abstract] [Full Text] [PDF]

				M.-N. Raymond, C. Bole-Feysot, Y. Banno, Z. Tanfin, and P. Robin Endothelin-1 Inhibits Apoptosis through a Sphingosine Kinase 1-Dependent Mechanism in Uterine Leiomyoma ELT3 Cells Endocrinology, December 1, 2006; 147(12): 5873 - 5882. [Abstract] [Full Text] [PDF]