TY - JOUR T1 - Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKIα Pathway JF - Molecular Pharmacology JO - Mol Pharmacol SP - 769 LP - 777 DO - 10.1124/mol.107.043125 VL - 73 IS - 3 AU - Patricia Monteiro AU - David Gilot AU - Eric Le Ferrec AU - Claudine Rauch AU - Dominique Lagadic-Gossmann AU - Olivier Fardel Y1 - 2008/03/01 UR - http://molpharm.aspetjournals.org/content/73/3/769.abstract N2 - Regulation of genes targeted by the ligand-activated aryl hydrocarbon receptor (AhR) has been shown to be controlled by calcium (Ca2+) changes induced by AhR agonists such as the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The present study was designed to characterize this link between Ca2+ and the AhR pathway. We report that fast elevation of intracellular Ca2+ in TCDD-exposed mammary MCF-7 cells was associated with transient enhanced activity of the Ca2+/calmodulin (CaM)-dependent protein kinase (CaMK) pathway. Chemical inhibition of this pathway using the CaM antagonist W7 or the CaMK inhibitor KN-93 strongly reduced TCDD-mediated induction of the AhR target gene CYP1A1. Small interfering RNA (siRNA)-mediated knockdown expression of CaMKIα, one of the CaMK isoforms, similarly prevented CYP1A1 up-regulation. Both KN-93 and siRNA targeting CaMKIα were found to abolish TCDD-mediated activation of CYP1A1 promoter and TCDD-triggered nuclear import of AhR, a crucial step of the AhR signaling pathway. TCDD-mediated inductions of various AhR targets, such as the drug metabolizing CYP1B1, the cytokine interleukin-1β, the chemokines interleukin-8 and CCL1, the adhesion molecule β7 integrin, and the AhR repressor, were also prevented by KN-93 in human macrophages. Taken together, these data identified the Ca2+/CaM/CaMKIα pathway as an important contributing factor to AhR-mediated genomic response. The American Society for Pharmacology and Experimental Therapeutics ER -