The interplay of the aryl hydrocarbon receptor and β-catenin alters both AhR-dependent transcription and Wnt/β-catenin signaling in liver progenitors
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
21602191
DOI
10.1093/toxsci/kfr129
PII: kfr129
Knihovny.cz E-resources
- MeSH
- Aryl Hydrocarbon Hydroxylases genetics metabolism MeSH
- beta Catenin genetics metabolism MeSH
- Cell Adhesion MeSH
- Cell Differentiation MeSH
- Cell Line MeSH
- Cytochrome P-450 CYP1A1 genetics metabolism MeSH
- Cytochrome P-450 CYP1B1 MeSH
- Down-Regulation drug effects MeSH
- Hepatocytes drug effects MeSH
- Liver drug effects MeSH
- Cadherins genetics MeSH
- Rats MeSH
- Polychlorinated Dibenzodioxins toxicity MeSH
- Rats, Inbred F344 MeSH
- Wnt Proteins genetics metabolism MeSH
- Receptors, Aryl Hydrocarbon genetics metabolism MeSH
- Wnt Signaling Pathway MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Aryl Hydrocarbon Hydroxylases MeSH
- beta Catenin MeSH
- Cyp1b1 protein, rat MeSH Browser
- Cytochrome P-450 CYP1A1 MeSH
- Cytochrome P-450 CYP1B1 MeSH
- Cadherins MeSH
- Polychlorinated Dibenzodioxins MeSH
- Wnt Proteins MeSH
- Receptors, Aryl Hydrocarbon MeSH
β-catenin is a key integrator of cadherin-mediated cell-cell adhesion and transcriptional regulation through the Wnt/β-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/β-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/β-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 β-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/β-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 β-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 β-catenin augmented the expression of selected AhR target genes, the persistent AhR activation may lead to downregulation of Wnt/β-catenin signaling, thus altering differentiation and/or proliferative status of liver progenitor cells.
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