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

Abstract

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.

The WNT/β-Catenin Pathway Is a Transcriptional Regulator ofCYP2E1,CYP1A2,and Aryl Hydrocarbon Receptor Gene Expression in Primary Human Hepatocytes

“…As this gene is ubiquitously expressed in most mammalian tissues (Le Carrour et al, 2010), its basal expression is likely to be b-catenin independent, and other transcription factors might contribute to its transcriptional regulation. Similar observations were reported using rat WB-F344 progenitors cells (Prochazkova et al, 2011).…”

“…Specifically, b-catenin may act as a coactivator of AhR in mouse hepatocytes , and AhR participates in b-catenin degradation in mouse intestine (Kawajiri et al, 2009). Moreover, sustained activation of AhR by TCDD reduces the level of b-catenin targets genes in WB-F344 cells (Prochazkova et al, 2011).…”

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

“…The AhR also binds STAT1, resulting in nuclear factor-kB promoter activity (Kimura et al, 2009). In addition, interactions of AhR have been described for the estrogen receptor, b-catenin, Nrf2, RelA, and RelB (Kim et al, 2000;Vogel et al, 2004Vogel et al, , 2007Miao et al, 2005;Braeuning et al, 2011;Procházková et al, 2011).…”

“…Of great scientific interest is the role that the AhR seems to play in progenitor cell expansion and differentiation in which the Wnt/b-catenin pathway is active (Laiosa et al, 2003;Singh et al, 2009;Boitano et al, 2010;Latchney et al, 2011;Procházková et al, 2011). Furthermore, a role for AhR in tissue regeneration has been described in models of liver, fin, and cardiac tissue regeneration (Mathew et al, 2006;Mitchell et al, 2006;Hofsteen et al, 2013).…”

Cooperation of structurally different aryl hydrocarbon receptor agonists and β-catenin in the regulation of CYP1A expression

“…Both signaling pathways synergize in the induction of AhR targets by TCDD in vitro Loeppen et al, 2005;Prochazkova et al, 2011). Mechanistic studies indicate that b-catenin and the AhR physically interact and that activation of b-catenin enhances the activity of the AhR at its binding sites on the DNA .…”