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Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKI Pathway

Institut National de la Santé et de la Recherche Médicale (INSERM U620), Equipe labellisée par la Ligue Nationale contre le Cancer (P.M., D.G., E.L., C.R., D.L.G., O.F.) and Université de Rennes 1, IFR140, Rennes, France (P.M, D.G., E.L., C.R., D.L.G., O.F.); and Department HITC, Hôpital Pontchaillou, CHU, Rennes, France (O.F.)

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 CaMKI, one of the CaMK isoforms, similarly prevented CYP1A1 up-regulation. Both KN-93 and siRNA targeting CaMKI 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/CaMKI pathway as an important contributing factor to AhR-mediated genomic response.

Address correspondence to: David Gilot, INSERM U620, Université de Rennes1, Faculté des Sciences Pharmaceutiques et Biologiques, IFR140, 2 Avenue du Professeur Léon Bernard, 35043 Rennes Cedex, France. E-mail: david.gilot{at}rennes.inserm.fr

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