Transcriptional activation of interleukin-8 by beta-catenin-Tcf4.
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.
Lévy
Laurence
L
Unité de Recombinaison et Expression Génétique (Inserm U163), Département de Médecine Moléculaire, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, France.
Neuveut
Christine
C
Renard
Claire-Angélique
CA
Charneau
Pierre
P
Branchereau
Sophie
S
Gauthier
Frederic
F
Van Nhieu
Jeanne Tran
JT
Cherqui
Daniel
D
Petit-Bertron
Anne-France
AF
Mathieu
Danièle
D
Buendia
Marie Annick
MA
D002465:Cell Movement; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000502:physiology*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D015854:Up-Regulation; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D016209:Interleukin-8; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin