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J. Biol. Chem., Vol. 277, Issue 44, 42386-42393, November 1, 2002

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Transcriptional Activation of Interleukin-8 by -Catenin-Tcf4^*

Laurence Lévy, Christine Neuveut, Claire-Angélique Renard, Pierre Charneau^§, Sophie Branchereau^¶, Frédéric Gauthier^¶, Jeanne Tran Van Nhieu, Daniel Cherqui^**, Anne-France Petit-Bertron, Danièle Mathieu^§§, and Marie Annick Buendia^¶¶

From the  Unité de Recombinaison et Expression Génétique (Inserm U163), ^§ Groupe de Virologie Moléculaire et Vectorologie, and  Unité Cytokines et Inflammation, Département de Médecine Moléculaire, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, ^¶ Service de Chirurgie Pédiatrique, Hôpital de Bicêtre, 94270 Le Kremlin-Bicêtre,  Département de Pathologie and ^** Service de Chirurgie Digestive, Hôpital Henri Mondor, AP-HP and University Paris 12, 94010 Créteil, and ^§§ Institut de Génétique Moléculaire, UMR 5535, IFR 24, 1919 Route de Mende, 34293 Montpellier, France

Nuclear translocation of -catenin and its association with Tcf/Lef factors are key steps in transduction of the Wnt signal, which is aberrantly activated in a variety of human cancers. In a search for new -catenin-Tcf target genes, we analyzed -catenin-induced alterations of gene expression in primary human hepatocytes, after transduction of either dominant stable -catenin or its truncated, transactivation-deficient counterpart by means of a lentiviral vector. cDNA microarray analysis revealed a limited set of up-regulated genes, including known Wnt targets such as matrilysin and keratin-1. In this screen, we identified the CXC chemokine interleukin 8 (IL-8) as a direct target of -catenin-Tcf4. IL-8 is constitutively expressed in various cancers, and it has been implicated in tumor progression through its mitogenic, motogenic, and angiogenic activities. The IL-8 promoter contains a unique consensus Tcf/Lef site that is critical for IL-8 activation by -catenin. We show here that the p300 coactivator was required for efficient transactivation of -catenin on this promoter. Ectopic expression of -catenin in hepatoma cells promoted IL-8 secretion, which stimulated endothelial cell migration. These data define IL-8 as a Wnt target and suggest that IL-8 induction by -catenin might be implicated in developmental and tumorigenic processes.

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