title: Coordinate regulation of cytochrome P450 1a1 expression in mouse liver by the aryl hydrocarbon receptor and the beta-catenin pathway.
abstract: The expression of cytochrome P450 (CYP) 1a1 and other drug-metabolizing enzymes is controlled by the aryl hydrocarbon receptor (AhR), which is activated by dioxin-type inducers leading to transcriptional induction of target genes. Here, we show that a second level of transcriptional control exists in hepatocytes, which is tightly linked to the Wnt/β-catenin/T-cell factor (TCF) signaling pathway. In transgenic mice, hepatic expression of CYP1A (and other CYP isoforms) is stimulated by the expression of mutationally activated β-catenin(S33Y) in the absence of AhR-activating compounds but repressed after knockout of β-catenin. These effects were further analyzed in vitro, and the stimulatory role of β-catenin was ascribed to a TCF-binding site within the CYP1A1 promoter. Moreover, β-catenin signaling acted cooperatively with AhR agonists via AhR-binding sites on the DNA during the induction of Cyp1a1 in vivo and in vitro. Activation of β-catenin enhanced the transactivation potential of ligand-activated AhR at its DNA-binding sites without altering the total amount of DNA-bound AhR. Coimmunoprecipitation demonstrated a physical interaction between AhR and β-catenin. Furthermore, the present results suggest that transcriptional induction of the AhR by β-catenin does not play a major role in β-catenin-dependent regulation of Cyp1a1 expression and that inhibition of β-catenin signaling by ligand-activated AhR, as recently observed in the intestine does not occur in mouse liver. In conclusion, signaling through β-catenin activates basal CYP1A1 expression and augments CYP1A1 induction by AhR ligands through enhancement of the transactivation potential of the AhR.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Tübingen, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.forename: Christoph
authors.initials: C
authors.lastname: Köhle
authors.forename: Albrecht
authors.initials: A
authors.lastname: Buchmann
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000201:enzymology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010957:Plasmids; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D018336:Receptors, Aryl Hydrocarbon; D051820:TCF Transcription Factors; D051176:beta Catenin; D019363:Cytochrome P-450 CYP1A1