2,3,7,8-Tetrachlorodibenzo-p-Dioxin Counteracts the p53 Response to a Genotoxicant by Upregulating Expression of the Metastasis Marker AGR2 in the Hepatocarcinoma Cell Line HepG2 - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Toxicological Sciences Année : 2010

2,3,7,8-Tetrachlorodibenzo-p-Dioxin Counteracts the p53 Response to a Genotoxicant by Upregulating Expression of the Metastasis Marker AGR2 in the Hepatocarcinoma Cell Line HepG2

Résumé

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is an environmental pollutant which binds the aryl hydrocarbon receptor (AhR), a transcription factor that triggers various biological responses. In this study, we show that TCDD treatment counteracts the p53 activation elicited by a genotoxic compound, etoposide, in the human hepatocarcinoma cell line HepG2 and we delineated the mechanisms of this interaction. Using siRNA knock-down experiments, we found that the newly described metastasis marker, anterior gradient-2 (AGR2), is involved in this effect. Both AGR2 mRNA and protein levels were increased (6-and 4-fold, respectively) by TCDD treatment and this effect was mediated by the AhR receptor. The half-life of AGR2 mRNA was unchanged by TCDD treatment. Analysis of the promoter of the AGR2 gene revealed 3 putative xenobiotic responsive elements (XRE) in the proximal 3.5 kb promoter. Transient transfection of HepG2 cells by the Gaussia luciferase reporter gene driven by various deleted and mutated fragments of the promoter indicated that only the most proximal XRE was active. These results suggest that AhR ligands such as TCDD may contribute to tumour progression by inhibiting p53 regulation by genotoxicants via the increased expression of the metastasis marker AGR2.
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Dates et versions

hal-02190079 , version 1 (21-07-2019)

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Ariane Ambolet-Camoit, Linh Chi Bui, Stéphane Pierre, Aline Chevallier, Alexandre Marchand, et al.. 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Counteracts the p53 Response to a Genotoxicant by Upregulating Expression of the Metastasis Marker AGR2 in the Hepatocarcinoma Cell Line HepG2. Toxicological Sciences, 2010, 115 (2), pp.501-512. ⟨10.1093/toxsci/kfq082⟩. ⟨hal-02190079⟩
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