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

By Laurence Levy, C. Neuveut, C. Renard, P. Charneau, S. Branchereau, F. Gauthier, J. T. van Nhieu, D. Cherqui, Anne-France Petit-Bertron, D. Mathieu and 1 more. Journal of Biological Chemistry, 2002

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Nuclear translocation of β-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 β-catenin-Tcf target genes, we analyzed β-catenin-induced alterations of gene expression in primary human hepatocytes, after transduction of either dominant stable β-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 β-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 β-catenin. We show here that the p300 coactivator was required for efficient transactivation of β-catenin on this promoter. Ectopic expression of β-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 β-catenin might be implicated in developmental and tumorigenic processes.

Subfields: Molecular Biology

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