The interplay of the aryl hydrocarbon receptor and beta-catenin alters both AhR-dependent transcription and Wnt/beta catenin signaling in liver progenitors.
|Druh||Článek v odborném periodiku|
|Časopis / Zdroj||Toxicological sciences|
|Fakulta / Pracoviště MU|
|Klíčová slova||Wnt signaling; dioxin; intercellular junctions; contact inhibition; liver progenitor cells; differentiation|
|Popis||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.|