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Research ArticleArticle

Xenobiotics and Loss of Cell Adhesion Drive Distinct Transcriptional Outcomes by Aryl Hydrocarbon Receptor Signaling

Nan Hao, Kian Leong Lee, Sebastian G.B. Furness, Cecilia Bosdotter, Lorenz Poellinger and Murray L. Whitelaw
Molecular Pharmacology August 30, 2012, mol.112.078873; DOI: https://doi.org/10.1124/mol.112.078873
Nan Hao
1 The University of Adelaide;
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Kian Leong Lee
2 National University of Singapore;
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Sebastian G.B. Furness
3 Monash University;
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Cecilia Bosdotter
4 Karolinska Institutet
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Lorenz Poellinger
2 National University of Singapore;
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Murray L. Whitelaw
1 The University of Adelaide;
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Abstract

The Aryl hydrocarbon Receptor (AhR) is a signal regulated transcription factor, which is canonically activated by the direct binding of xenobiotics. In addition, switching cells from adherent to suspension culture also activates the AhR, representing a non-xenobiotic, physiological activation of AhR signaling. Here, we show that the AhR is recruited to target gene enhancers in both ligand (YH439) treated and suspension cells, suggesting a common mechanism of target gene induction between these two routes of AhR activation. However, gene expression profiles critically differ between xenobiotic and suspension activated AhR signaling. Por and Cldnd1 were regulated predominately by ligand treatments, while in contrast, ApoER2 and Ganc were regulated predominately by the suspension condition. Classic xenobiotic metabolizing AhR targets such as Cyp1a1, Cyp1b1, and Nqo1 were regulated by both ligand and suspension conditions. Temporal expression patterns of AhR target genes were also found to vary, with examples of transient activation, transient repression, or sustained alterations in expression. Furthermore, sequence analysis coupled with ChIP assays and reporter gene analysis identified a functional XRE (xenobiotic response element) in the intron1 of mouse Tiparp gene, which was also bound by HIF-1α during hypoxia, and features a concatemer of 4 XRE cores (GCGTG). Our data suggest that this XRE concatemer site concurrently regulates the expression of both Tiparp gene and its cis anti-sense non-coding RNA following ligand or suspension induced AhR activation. This work lends novel insights into how AhR signaling drives different transcriptional programs via the ligand versus suspension modes of activation.

  • DNA binding sites
  • Promoter analysis
  • Cytochrome P450
  • Regulation - physiological
  • Regulation - transcriptional
  • Regulation - xenobiotic
  • Received March 22, 2012.
  • Revision received August 28, 2012.
  • Accepted August 30, 2012.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 104 (6)
Molecular Pharmacology
Vol. 104, Issue 6
1 Dec 2023
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Research ArticleArticle

Xenobiotics and Loss of Cell Adhesion Drive Distinct Transcriptional Outcomes by Aryl Hydrocarbon Receptor Signaling

Nan Hao, Kian Leong Lee, Sebastian G.B. Furness, Cecilia Bosdotter, Lorenz Poellinger and Murray L. Whitelaw
Molecular Pharmacology August 30, 2012, mol.112.078873; DOI: https://doi.org/10.1124/mol.112.078873

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Research ArticleArticle

Xenobiotics and Loss of Cell Adhesion Drive Distinct Transcriptional Outcomes by Aryl Hydrocarbon Receptor Signaling

Nan Hao, Kian Leong Lee, Sebastian G.B. Furness, Cecilia Bosdotter, Lorenz Poellinger and Murray L. Whitelaw
Molecular Pharmacology August 30, 2012, mol.112.078873; DOI: https://doi.org/10.1124/mol.112.078873
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