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

Abstract

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

Transactivation of MCP‐1/CCL2 by β‐catenin/TCF‐4 in human breast cancer cells

“…34 This endogenous level of nuclear b-catenin might thus be sufficient to activate the MCP-1 promoter in the presence of TCF-4. In agreement with ours results, Levy et al 32 have shown that, in hepatoma cells containing a constitutively activated bcatenin allele, exogenous wild-type TCF-4 is sufficient to activate the IL-8 promoter. In contrast, the deleted form of TCF-4 which lacks the b-catenin binding domain (DNTCF-4) was unable to activate this promoter.…”

“…More particularly in agreement with our observations, other chemokines, including IL-8/CXCL8, another angiogenic chemokine, and MCP-3/CCL7, have been shown to be regulated by the b-catenin/TCF pathway. 32,63 The proangiogenic vascular endothelial growth factor (VEGF) has also been shown to be regulated by the b-catenin/TCF pathway.…”

“…), some of them having important implications in cancer progression. [27][28][29][30][31][32][33][34][35][36] These independent data from the literature therefore suggest that a reorganisation of E-cadherin/b-catenin and an overexpression of MCP-1 in tumour cells are 2 events associated with cancer progression. This prompted us to investigate the potential regulation of MCP-1 by the b-catenin/TCF pathway.…”

Augmentation of Therapeutic Angiogenesis Using Genetically Modified Human Endothelial Progenitor Cells with Altered Glycogen Synthase Kinase-3β Activity

“…Transduction of GSK3␤-KM also enhanced secretion of IL-8 in early and late EPC. This could be explained by up-regulation of IL-8 by ␤-catenin, which is downstream of GSK3␤ (42). Conversely, GSK3␤-KM promoted the differentiation of late EPC, but early EPC did not exhibit this property.…”

“Soft” tissue patterning: Muscles and tendons of the limb take their form

“…PDGFB is secreted as vessels develop throughout the limb, leading to the up-regulation of extracellular matrix and connective tissue markers, including Tcf4. In turn, Tcf4 participates in the recruitment of endothelial cells (Levy et al, 2002). As a consequence, a positive feedback loop is generated in which extracellular matrix proteins and Tcf4 are up-regulated along the length of the vessel at the expense of muscle formation.…”