RRC ID 27178
Author Braeuning A, Köhle C, Buchmann A, Schwarz M.
Title Coordinate regulation of cytochrome P450 1a1 expression in mouse liver by the aryl hydrocarbon receptor and the beta-catenin pathway.
Journal Toxicol Sci
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.
Volume 122(1)
Pages 16-25
Published 2011-7-1
DOI 10.1093/toxsci/kfr080
PII kfr080
PMID 21498875
MeSH Animals Blotting, Western Cells, Cultured Chromatin Immunoprecipitation Cytochrome P-450 CYP1A1 / genetics Cytochrome P-450 CYP1A1 / metabolism* Gene Expression Regulation* Hepatocytes / enzymology Isoenzymes / genetics Isoenzymes / metabolism Liver / cytology Liver / metabolism* Male Mice Mice, Inbred C3H Mice, Knockout Mice, Transgenic Plasmids Receptors, Aryl Hydrocarbon / genetics* Receptors, Aryl Hydrocarbon / metabolism Signal Transduction TCF Transcription Factors / genetics TCF Transcription Factors / metabolism Transcriptional Activation Wnt Signaling Pathway beta Catenin / genetics* beta Catenin / metabolism
IF 3.703
Times Cited 53
WOS Category TOXICOLOGY
Resource
DNA material pCALNL5 (RDB01862)