Transcriptional activation of interleukin-8 by beta-catenin-Tcf4

• Published in: The Journal of biological chemistry 2002-11, Vol.277 (44), p.42386-42393
• Main Authors: Lévy, Laurence, Neuveut, Christine, Renard, Claire-Angélique, Charneau, Pierre, Branchereau, Sophie, Gauthier, Frederic, Van Nhieu, Jeanne Tran, Cherqui, Daniel, Petit-Bertron, Anne-France, Mathieu, Danièle, Buendia, Marie Annick
• Format: Article
• Language: English
• Subjects: beta Catenin; Biochemistry, Molecular Biology; Cell Movement; Cells, Cultured; Cytoskeletal Proteins - physiology; Endothelium, Vascular - cytology; Hepatocytes - metabolism; Humans; Interleukin-8 - biosynthesis; Interleukin-8 - genetics; Interleukin-8 - metabolism; Life Sciences; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; TCF Transcription Factors; Trans-Activators - physiology; Transcription Factor 7-Like 2 Protein; Transcription Factors - physiology; Transcriptional Activation; Up-Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M207418200

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