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Accelerated Communication

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

Department of Biomedical Sciences Division of Cancer Biology (S.E.E) and Graduate Program in Pharmacology (Y.R.D.), Meharry Medical College, Nashville, Tennessee

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.

Address correspondence to: Dr. Sakina Eltom, 1005 Dr. D.B. Todd Blvd, Nashville, TN 37208, Tel/Fax: (615) 327-5713, seltom{at}mmc.edu

This article has been cited by other articles:

				P. Monteiro, D. Gilot, E. Le Ferrec, C. Rauch, D. Lagadic-Gossmann, and O. Fardel Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKI{alpha} Pathway Mol. Pharmacol., March 1, 2008; 73(3): 769 - 777. [Abstract] [Full Text] [PDF]

				R. S. Pollenz Comments on "Calpain Mediates the Dioxin-Induced Activation and Down-Regulation of the Aryl Hydrocarbon Receptor" Mol. Pharmacol., January 1, 2007; 71(1): 384 - 385. [Full Text] [PDF]

				S. E. Eltom and Y. Dale Response to Comments on "Calpain Mediates the Dioxin-Induced Activation and Down-Regulation of the Aryl Hydrocarbon Receptor" Mol. Pharmacol., January 1, 2007; 71(1): 386 - 387. [Full Text] [PDF]