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Molecular Pharmacology

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Calpain Mediates the Dioxin-Induced Activation and Down-Regulation of the Aryl Hydrocarbon Receptor

Yolanda R. Dale and Sakina E. Eltom
Molecular Pharmacology November 2006, 70 (5) 1481-1487; DOI: https://doi.org/10.1124/mol.106.027474
Yolanda R. Dale
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Sakina E. Eltom
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Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix transcription factor that binds polyaromatic hydrocarbons (PAH), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and mediates their toxicity. Binding of PAH to AhR in the cytoplasm triggers a poorly defined transformation step of the receptor into a nuclear transcription factor. In this study, we show that the calcium-dependent cysteine protease calpain plays a major role in the ligand-induced transformation and signaling of AhR. Fluorescence imaging measurements showed that TCDD treatment elevates intracellular calcium, providing the trigger for calpain activation, as measured toward t-butoxycarbonyl-Leu-Met-chloromethylaminocoumarin, a calpain-specific substrate. Inhibition of calpain activity by the N-benzyloxycarbonyl-Val-Phe-aldehyde (MDL28170) blocked the TCDD-induced nuclear translocation of AhR in Hepa1c1c7 mouse hepatoma cell line. Treatment of the human metastatic breast carcinoma cell line MT-2 with MDL28170 and 3-(4-iodophenyl)-2-mercapto-(Z)-2-propenoic acid (PD 150606), two calpain-selective inhibitors, completely abolished the TCDD-induced transactivation of AhR as assessed by transcription of CYP1A1 gene. Previous studies have established that after TCDD-induced transactivation, the AhR undergoes a massive depletion; we show here that selective calpain inhibitors can block this step, which suggests that the ligand-induced down-regulation of the AhR is calpain-dependent. The data presented support a major role for calpain in the AhR transformation, transactivation, and subsequent down-regulation, and provide a possible explanation for many of the reported phenomena of ligand-independent activation of AhR.

Footnotes

  • This research was funded in part by National Institutes of Health (NIH) grants RR03032-15 and CA91408 and Department of Defense grant DAMD17-02-01-0483 (to S.E.E.). Y.D. was supported through NIH grants R25-GM59994 and T32-CA09592.

  • ABBREVIATIONS: AhR, aryl hydrocarbon receptor; PAH, polyaromatic hydrocarbons; hsp90, 90-kDa heat shock protein; ARNT, aryl hydrocarbon receptor nuclear translocator; MDL 28170, N-benzyloxycarbonyl-Val-Phe-aldehyde; PD 150606, 3-(4-iodophenyl)-2-mercapto-(Z)-2-propenoic acid; MG-132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; BOC-LM-CMAC, t-butoxycarbonyl-Leu-Met-chloromethylaminocoumarin; AM, acetoxymethyl; PCR, polymerase chain reaction; DMSO, dimethyl sulfoxide; TBST, Tris-buffered saline-Tween 20.

    • Received June 5, 2006.
    • Accepted August 4, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (5)
Molecular Pharmacology
Vol. 70, Issue 5
1 Nov 2006
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OtherAccelerated Communication

Calpain Mediates the Dioxin-Induced Activation and Down-Regulation of the Aryl Hydrocarbon Receptor

Yolanda R. Dale and Sakina E. Eltom
Molecular Pharmacology November 1, 2006, 70 (5) 1481-1487; DOI: https://doi.org/10.1124/mol.106.027474

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OtherAccelerated Communication

Calpain Mediates the Dioxin-Induced Activation and Down-Regulation of the Aryl Hydrocarbon Receptor

Yolanda R. Dale and Sakina E. Eltom
Molecular Pharmacology November 1, 2006, 70 (5) 1481-1487; DOI: https://doi.org/10.1124/mol.106.027474
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