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 Writ 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.
Transcriptional activation of interleukin-8 by beta-catenin-Tcf4
Levy, L.; Neuveut, C.; Renard, C. A.; Charneau, P.; Branchereau, S.; Gauthier, F.; Van Nhieu, J. T.; Cherqui, D.; Petit-Bertron, A. F.; Mathieu, D.; Buendia, M. A.
Journal of Biological Chemistry
2002-11-01 / vol 277 / pages 42386-42393
expression; cyclin d1; cells; transgenic mice; beta-catenin; colon-carcinoma; colorectal carcinomas; endothelial growth-factor; human hepatocellular-carcinoma; target