PT  - JOURNAL ARTICLE
AU  - Patricia Monteiro
AU  - David Gilot
AU  - Eric Le Ferrec
AU  - Claudine Rauch
AU  - Dominique Lagadic-Gossmann
AU  - Olivier Fardel
TI  - Dioxin-Mediated Up-Regulation of Aryl Hydrocarbon Receptor Target Genes Is Dependent on the Calcium/Calmodulin/CaMKIα Pathway
AID  - 10.1124/mol.107.043125
DP  - 2008 Mar 01
TA  - Molecular Pharmacology
PG  - 769--777
VI  - 73
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/73/3/769.short
4100  - http://molpharm.aspetjournals.org/content/73/3/769.full
SO  - Mol Pharmacol2008 Mar 01; 73
AB  - 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