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Cell Growth & Differentiation Vol. 11, 573-580, November 2000
© 2000 American Association for Cancer Research


Articles

Erythropoietin Induction of Tissue Inhibitors of Metalloproteinase-1 Expression and Secretion Is Mediated by Mitogen-activated Protein Kinase and Phosphatidylinositol 3-kinase Pathways1

Zahra Kadri, Emmanuelle Petitfrère, Cédric Boudot, Jean-Marc Freyssinier, Serge Fichelson, Patrick Mayeux, Hervé Emonard, William Hornebeck, Bernard Haye and Claudine Billat2

Laboratoire de Biochimie, Centre National de la Recherche Scientifique Formation de Recherche en Evolution 2260, Institut Fédératif de Recherche 53 Biomolécules, UFR Sciences Exactes et Naturelles, UFR de Medecine, Université de Reims Champagne-Ardenne, F51687 Reims Cedex 2, France [Z. K., E. P., C. B., H. E., W. H., B. H., C. B.], Laboratoire d’ hématopoïèse, Site Transfusionnel Cochin [J-M. F., S. F.], Institut Cochin de Génétique Moléculaire, Institut National de la Santé et de la Recherche Médicale U363, Université René Descartes [P. M.], Hôpital Cochin, F57014 Paris, France

Abstract

In the present study, we demonstrate that erythropoietin (Epo) induces the expression and the release of tissue inhibitors of metalloproteinase-1 (TIMP-1) in a time- and dose-dependent manner in Epo-dependent cell line UT-7 cells and in normal human erythroid progenitor cells from cord blood (CD36+) and required de novo protein synthesis. TIMP-1 was not expressed in the absence of Epo. Inhibition of the mitogen-activated protein kinase pathway by the specific inhibitors PD98059 and U0126 and of phosphatidylinositol 3-kinase by LY294002, strongly inhibited Epo-induced TIMP-1 expression and secretion. In the absence of Epo, both latent and active forms of matrix metalloproteinase-9 (MMP-9) were secreted into media. Upon Epo stimulation, MMP-9 and pro-MMP-9 secretion was inhibited in a dose-dependent manner parallel to TIMP-1 induction. The addition of PD98059, U0126, and LY294002 in the presence of Epo restored MMP-9 production in UT-7 and CD36+ cells. Our findings strongly suggest an inversely coordinated regulation of the TIMP-1 gene and MMP-9 production by Epo via mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways.




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Molecular Cancer Research Cell Growth & Differentiation
Copyright © 2000 by the American Association of Cancer Research.