期刊
TOXICOLOGICAL SCIENCES
卷 122, 期 2, 页码 349-360出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfr129
关键词
Wnt signaling; dioxin; intercellular junctions; contact inhibition; liver progenitor cells; differentiation
类别
资金
- Czech Science Foundation [524/09/1337]
- Academy of Sciences of the Czech Republic [AV0Z50040507, AV0Z50040702]
- Ministry of Education Youth and Sports of the Czech Republic [MSM 0021622430]
- Czech Ministry of Agriculture [MZE0002716202]
- EMBO [204/09/H058]
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.
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