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.
Unité de Recombinaison et Expression Génétique (Inserm U163), Département de Médecine Moléculaire, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, France.
Laurence
L
Lévy
Christine
C
Neuveut
Claire-Angélique
CA
Renard
Pierre
P
Charneau
Sophie
S
Branchereau
Frederic
F
Gauthier
Jeanne Tran
JT
Van Nhieu
Daniel
D
Cherqui
Anne-France
AF
Petit-Bertron
Danièle
D
Mathieu
Marie Annick
MA
Buendia
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