The Interplay of the Aryl Hydrocarbon Receptor and beta-Catenin Alters Both AhR-Dependent Transcription and Wnt/beta-Catenin Signaling in Liver Progenitors

Časopis: TOXICOLOGICAL SCIENCES 122, 349-360
Autoři: Prochazkova, J., Kabatkova, M., Bryja, V., Umannova, L., Bernatik, O., Kozubik, A., Machala, M., Vondracek, J.
Rok: 2011

Abstrakt

beta-Catenin is a key integrator of cadherin-mediated cell-cell adhesion and transcriptional regulation through the Wnt/beta-catenin pathway, which plays an important role in liver biology. Using a model of contact-inhibited liver progenitor cells, we examined the interactions of Wnt/beta-catenin signaling with the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, which mediates the toxicity of dioxin-like compounds, including their effects on development and hepatocarcinogenesis. We found that AhR and Wnt/beta-catenin cooperated in the induction of AhR transcriptional targets, such as Cyp1a1 and Cyp1b1. However, simultaneously, the activation of AhR led to a decrease of dephosphorylated active beta-catenin pool, as well as to hypophosphorylation of Dishevelled, participating in regulation of Wnt signaling. A sustained AhR activation by its model ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), led to a downregulation of a number of Wnt/beta-catenin pathway target genes. TCDD also induced a switch in cytokeratin expression, where downregulation of cytokeratins 14 and 19 was accompanied with an increased cytokeratin 8 expression. Together with a downregulation of additional markers associated with stem-like phenotype, this indicated that the AhR activation interfered with differentiation of liver progenitors. The downregulation of beta-catenin was also related to a reduced cell adhesion, disruption of E-cadherin-mediated cell-cell junctions and an increased G1-S transition in liver progenitor cell line. In conclusion, although beta-catenin augmented the expression of selected AhR target genes, the persistent AhR activation may lead to downregulation of Wnt/beta-catenin signaling, thus altering differentiation and/or proliferative status of liver progenitor cells.