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Molecular Pharmacology

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Research ArticleArticle

A Dioxin-Responsive Enhancer 3′ of the Human CYP1A2 Gene

Steven T. Okino, Linda C. Quattrochi, Deepa Pookot, Mieko Iwahashi and Rajvir Dahiya
Molecular Pharmacology December 2007, 72 (6) 1457-1465; DOI: https://doi.org/10.1124/mol.107.039826
Steven T. Okino
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Linda C. Quattrochi
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Deepa Pookot
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Mieko Iwahashi
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Rajvir Dahiya
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Abstract

The human CYP1A genes CYP1A1 and CYP1A2 are in a head-to-head orientation on chromosome 15. Both CYP1A genes and CYP1B1 are transcriptionally induced by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that binds 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin). Although the TCDD-responsive enhancers for CYP1A1 and CYP1B1 are well characterized, a similar CYP1A2 enhancer has not been identified. In the human prostate cell line RWPE-1, CYP1A2 mRNA expression is dramatically induced by TCDD. Therefore, analysis of the native CYP1A2 gene in these cells can provide insight into its induction mechanism. To identify sites that may bind AhR on the CYP1A locus, we scanned 75 kilobases of chromosome 15 sequence for high-affinity AhR binding sites. We then analyzed most of the sites for TCDD-inducible AhR interaction by chromatin immunoprecipitation. As expected, the CYP1A1 and CYP1B1 enhancers bind AhR in TCDD-treated cells. It is noteworthy that we identify a region 3′ of CYP1A2 that also binds AhR in response to TCDD. We cannot detect AhR binding at other sites on the CYP1A locus. In vivo footprinting demonstrates that two AhR binding sites in the CYP1A2 3′ region are occupied in TCDD-treated cells. Reporter-gene studies show that these sites confer TCDD-responsiveness to a heterologous promoter. AhR also binds to the CYP1A2 3′ region in TCDD-treated LS180 cells but not in HepG2 and ND-1 cells. In the latter cell lines, the CYP1A2 3′ region is extensively methylated. In summary, we identify a novel TCDD-responsive enhancer for CYP1A2. We were surprised to find that this enhancer is not conserved across species and is primarily human-specific.

Footnotes

  • National Institutes of Health grants RO1CA101844, RO1CA111470, RO1CA108612, RO1AG21418, and T32DK07790, Veteran's Affairs Merit Review, and REAP grants.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.039826.

  • ABBREVIATIONS: PAH, polycyclic aromatic hydrocarbon; AhR, aryl hydrocarbon receptor; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; DRE, dioxin-response element; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ChIP, chromatin immunoprecipitation; DMS, dimethyl sulfate; DMSO, dimethyl sulfoxide; PCR, polymerase chain reaction; ARNT, aryl hydrocarbon receptor nuclear translocator; kb, kilobase(s); bp, base pair(s).

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received July 9, 2007.
    • Accepted September 4, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (6)
Molecular Pharmacology
Vol. 72, Issue 6
1 Dec 2007
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Research ArticleArticle

A Dioxin-Responsive Enhancer 3′ of the Human CYP1A2 Gene

Steven T. Okino, Linda C. Quattrochi, Deepa Pookot, Mieko Iwahashi and Rajvir Dahiya
Molecular Pharmacology December 1, 2007, 72 (6) 1457-1465; DOI: https://doi.org/10.1124/mol.107.039826

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Research ArticleArticle

A Dioxin-Responsive Enhancer 3′ of the Human CYP1A2 Gene

Steven T. Okino, Linda C. Quattrochi, Deepa Pookot, Mieko Iwahashi and Rajvir Dahiya
Molecular Pharmacology December 1, 2007, 72 (6) 1457-1465; DOI: https://doi.org/10.1124/mol.107.039826
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