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Research ArticleArticle

Identification of a Functional Antioxidant Response Element within the Eighth Intron of the Human ABCC3 Gene

Mark J. Canet, Matthew D. Merrell, Bryan G. Harder, Jonathan M. Maher, Tongde Wu, Andrew J. Lickteig, Jonathan P. Jackson, Donna D. Zhang, Masayuki Yamamoto and Nathan J. Cherrington
Drug Metabolism and Disposition January 2015, 43 (1) 93-99; DOI: https://doi.org/10.1124/dmd.114.060103
Mark J. Canet
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., M.D.M., B.G.H. T.W., A.J.L., J.P.J., D.D.Z, N.J.C.); and Department of Medical Biochemistry, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan (J.M.M., M.Y.)
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Matthew D. Merrell
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., M.D.M., B.G.H. T.W., A.J.L., J.P.J., D.D.Z, N.J.C.); and Department of Medical Biochemistry, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan (J.M.M., M.Y.)
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Bryan G. Harder
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., M.D.M., B.G.H. T.W., A.J.L., J.P.J., D.D.Z, N.J.C.); and Department of Medical Biochemistry, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan (J.M.M., M.Y.)
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Jonathan M. Maher
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., M.D.M., B.G.H. T.W., A.J.L., J.P.J., D.D.Z, N.J.C.); and Department of Medical Biochemistry, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan (J.M.M., M.Y.)
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Tongde Wu
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., M.D.M., B.G.H. T.W., A.J.L., J.P.J., D.D.Z, N.J.C.); and Department of Medical Biochemistry, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan (J.M.M., M.Y.)
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Andrew J. Lickteig
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., M.D.M., B.G.H. T.W., A.J.L., J.P.J., D.D.Z, N.J.C.); and Department of Medical Biochemistry, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan (J.M.M., M.Y.)
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Jonathan P. Jackson
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., M.D.M., B.G.H. T.W., A.J.L., J.P.J., D.D.Z, N.J.C.); and Department of Medical Biochemistry, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan (J.M.M., M.Y.)
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Donna D. Zhang
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., M.D.M., B.G.H. T.W., A.J.L., J.P.J., D.D.Z, N.J.C.); and Department of Medical Biochemistry, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan (J.M.M., M.Y.)
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Masayuki Yamamoto
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., M.D.M., B.G.H. T.W., A.J.L., J.P.J., D.D.Z, N.J.C.); and Department of Medical Biochemistry, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan (J.M.M., M.Y.)
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Nathan J. Cherrington
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (M.J.C., M.D.M., B.G.H. T.W., A.J.L., J.P.J., D.D.Z, N.J.C.); and Department of Medical Biochemistry, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan (J.M.M., M.Y.)
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Abstract

The ATP-binding cassette (ABC) family of transporters, including ABCC3, is a large family of efflux pumps that plays a pivotal role in the elimination of xenobiotics from the body. ABCC3 has been reported to be induced during hepatic stress conditions and through the progression of some forms of cancer. Several lines of evidence have implicated the transcription factor nuclear factor (erythroid-derived 2)–like 2 (Nrf2) in this induction. However, although rodent models have been investigated, a functional antioxidant response element (ARE) in the human ABCC3 gene has not been identified. The purpose of this study was to identify and characterize the ARE(s) responsible for mediating the Nrf2-dependent induction of the human ABCC3 gene. A high-throughput chromatin immunoprecipitation-sequencing analysis performed in A549 cells revealed a specific interaction between Nrf2 and the eighth intron of the human ABCC3 gene rather than the more prototypical flanking region of the gene. Subsequent in silico analysis of the intron identified two putative ARE elements that contained the core consensus ARE sequence commonly found in several Nrf2-responsive genes. Functional characterization of these two AREs using luciferase-reporter constructs with ARE mutant constructs revealed that one of these putative AREs is functionally active. Finally, DNA pull-down assays confirmed specific binding of these intronic AREs by Nrf2 in vitro. Our findings identify a functional Nrf2 response element within the eighth intron of the ABCC3 gene, which may provide mechanistic insight into the induction of ABCC3 during antioxidant response stimuli.

Footnotes

    • Received July 21, 2014.
    • Accepted October 27, 2014.
  • M.J.C. and M.D.M. both contributed equally to this work.

  • This work was supported by the National Institutes of Health [Grants AI083927, ES006694, and HD062489], National Institute of Environmental Health Science Toxicology Training [Grant ES007091], and the National Science Foundation of Arizona.

  • dx.doi.org/10.1124/dmd.114.060103

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (1)
Drug Metabolism and Disposition
Vol. 43, Issue 1
1 Jan 2015
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Research ArticleArticle

Characterization of Antioxidant Response Elements in ABCC3 Gene

Mark J. Canet, Matthew D. Merrell, Bryan G. Harder, Jonathan M. Maher, Tongde Wu, Andrew J. Lickteig, Jonathan P. Jackson, Donna D. Zhang, Masayuki Yamamoto and Nathan J. Cherrington
Drug Metabolism and Disposition January 1, 2015, 43 (1) 93-99; DOI: https://doi.org/10.1124/dmd.114.060103

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Research ArticleArticle

Characterization of Antioxidant Response Elements in ABCC3 Gene

Mark J. Canet, Matthew D. Merrell, Bryan G. Harder, Jonathan M. Maher, Tongde Wu, Andrew J. Lickteig, Jonathan P. Jackson, Donna D. Zhang, Masayuki Yamamoto and Nathan J. Cherrington
Drug Metabolism and Disposition January 1, 2015, 43 (1) 93-99; DOI: https://doi.org/10.1124/dmd.114.060103
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