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Int. J. Mol. Sci. 2014, 15(4), 6475-6487;

Functional Analysis of the Dioxin Response Elements (DREs) of the Murine CYP1A1 Gene Promoter: Beyond the Core DRE Sequence

Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
Foreign Economic Cooperation Office, Ministry of Environmental Protection, Beijing 100035, China
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 3 January 2014 / Revised: 1 February 2014 / Accepted: 7 February 2014 / Published: 16 April 2014
(This article belongs to the Special Issue Mechanisms of Toxicity of Dioxins and Related Compounds)
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The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the biological and toxicological effects of halogenated aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). When activated by dioxin, the cytosolic AhR protein complex translocates into the nucleus and dimerizes with the ARNT (Ah receptor nuclear translocator) protein. The heteromeric ligand:AhR/Arnt complex then recognizes and binds to its specific DNA recognition site, the dioxin response element (DRE). DREs are located upstream of cytochrome P4501A1 (CYP1A1) and other AhR-responsive genes, and binding of the AhR complex stimulates their transcription. Although CYP1A1 expression has been used as the model system to define the biochemical and molecular mechanism of AhR action, there is still limited knowledge about the roles of each of the seven DREs located in the CYP1A1 promoter. These seven DREs are conserved in mouse, human and rat. Deletion analysis showed that a single DRE at -488 was enough to activate the transcription. Truncation analysis demonstrated that the DRE at site -981 has the highest transcriptional efficiency in response to TCDD. This result was verified by mutation analysis, suggesting that the conserved DRE at site -981 could represent a significant and universal AhR regulatory element for CYP1A1. The reversed substituted intolerant core sequence (5'-GCGTG-3' or 5'-CACGC-3') of seven DREs reduced the transcriptional efficiency, which illustrated that the adjacent sequences of DRE played a vital role in activating transcription. The core DRE sequence (5'-TNGCGTG-3') tends to show a higher transcriptional level than that of the core DRE sequence (5'-CACGCNA-3') triggered by TCDD. Furthermore, in the core DRE (5'-TNGCGTG-3') sequence, when “N” is thymine or cytosine (T or C), the transcription efficiency was stronger compared with that of the other nucleotides. The effects of DRE orientation, DRE adjacent sequences and the nucleotide “N” in the core DRE (5'-TNGCGTG-3') sequence on the AhR-regulated CYP1A1 transcription in response to TCDD were studied systematically, and our study laid a good foundation for further investigation into the AhR-dependent transcriptional regulation triggered by dioxin and dioxin-like compounds. View Full-Text
Keywords: aryl hydrocarbon receptor (AhR); dioxin responsive element (DRE); 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); transcriptional regulation aryl hydrocarbon receptor (AhR); dioxin responsive element (DRE); 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); transcriptional regulation
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Li, S.; Pei, X.; Zhang, W.; Xie, H.Q.; Zhao, B. Functional Analysis of the Dioxin Response Elements (DREs) of the Murine CYP1A1 Gene Promoter: Beyond the Core DRE Sequence. Int. J. Mol. Sci. 2014, 15, 6475-6487.

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