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Molecular Pharmacology

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Research ArticleArticle

Superinduction of CYP1A1 in MCF10A Cultures by Cycloheximide, Anisomycin, and Puromycin: A Process Independent of Effects on Protein Translation and Unrelated to Suppression of Aryl Hydrocarbon Receptor Proteolysis by the Proteasome

Aby Joiakim, Patricia A. Mathieu, Althea A. Elliott and John J. Reiners Jr.
Molecular Pharmacology October 2004, 66 (4) 936-947; DOI: https://doi.org/10.1124/mol.66.4.936
Aby Joiakim
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Patricia A. Mathieu
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Althea A. Elliott
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John J. Reiners Jr.
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Abstract

Exposure of the human breast epithelial cell line MCF10A to ≥1 μg/ml cycloheximide (CHX)-induced accumulations of CYP1A1 mRNA 6-fold greater than that achieved with only 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Cotreatment with CHX and TCDD caused superinduction of CYP1A1 with accumulations of CYP1A1 mRNA 30-fold greater than that achieved with only TCDD. Similar results were obtained with the protein translation inhibitors anisomycin (ANS) and puromycin (PUR). Intra- and interinhibitor comparisons of dose/concentration response curves demonstrated the absence of a quantitative relationship between [3H]leucine incorporation and CYP1A1 induction/superinduction. The inducing/superinducing activities of CHX were suppressed by coincubation with the aryl hydrocarbon receptor (AhR) antagonists α-naphthoflavone and 3′-methoxy-4′-nitroflavone (PD168641). Electrophoretic mobility shift assays demonstrated that nuclear extracts from CHX-treated and CHX + TCDD cotreated cultures formed ∼58 and ∼340% of the AhR/DNA complexes obtained with TCDD-treated cultures, respectively. In contrast, rat liver extracts did not form AhR/DNA complexes after in vitro transformation with CHX. AhR turnover in TCDD-treated hepatoma 1c1c7 cultures was suppressed by cotreatment with CHX. In contrast, CHX or ANS treatment of MCF10A cultures induced AhR loss and enhanced AhR loss in cultures cotreated with TCDD. Cotreatment with N-benzoyloxycarbonyl-(Z)-Leu-Leu-leucinal (MG132) but not leptomycin B suppressed AhR loss. Hence, in MCF10A cells, CHX is not an AhR agonist but can superinduce CYP1A1 via an AhR-dependent mechanism; CYP1A1 superinduction by translation inhibitors is neither quantitatively related to effects on protein synthesis nor due to a generalized prevention of AhR proteolysis, and proteasome-mediated degradation of the activated AhR can occur in the nucleus.

  • Received October 7, 2003.
  • Accepted June 24, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (4)
Molecular Pharmacology
Vol. 66, Issue 4
1 Oct 2004
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Research ArticleArticle

Superinduction of CYP1A1 in MCF10A Cultures by Cycloheximide, Anisomycin, and Puromycin: A Process Independent of Effects on Protein Translation and Unrelated to Suppression of Aryl Hydrocarbon Receptor Proteolysis by the Proteasome

Aby Joiakim, Patricia A. Mathieu, Althea A. Elliott and John J. Reiners
Molecular Pharmacology October 1, 2004, 66 (4) 936-947; DOI: https://doi.org/10.1124/mol.66.4.936

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Research ArticleArticle

Superinduction of CYP1A1 in MCF10A Cultures by Cycloheximide, Anisomycin, and Puromycin: A Process Independent of Effects on Protein Translation and Unrelated to Suppression of Aryl Hydrocarbon Receptor Proteolysis by the Proteasome

Aby Joiakim, Patricia A. Mathieu, Althea A. Elliott and John J. Reiners
Molecular Pharmacology October 1, 2004, 66 (4) 936-947; DOI: https://doi.org/10.1124/mol.66.4.936
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