論文 - 詳細
| RRC ID | 27178 |
|---|---|
| 著者 | Braeuning A, Köhle C, Buchmann A, Schwarz M. |
| タイトル | Coordinate regulation of cytochrome P450 1a1 expression in mouse liver by the aryl hydrocarbon receptor and the beta-catenin pathway. |
| ジャーナル | 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. |
| 巻・号 | 122(1) |
| ページ | 16-25 |
| 公開日 | 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 |
| 引用数 | 53 |
| WOS 分野 | TOXICOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| 遺伝子材料 | pCALNL5 (RDB01862) |