Negative regulation of aryl hydrocarbon receptor by its lysine mutations and exposure to nickel

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Aryl Hydrocarbon Receptor (AhR) is a nuclear receptor for many environmental toxicants including TCDD. It mediates the induction of many metabolic enzymes of the cytochrome P450 family after engaging with its ligands. Meanwhile, nickel, also an environmental toxicant, induces a hypoxic response, leading to stabilization of HIF-1α. Lysine residues known for posttranslational modifications are important for subcellular localization, stability, and/or activity of gene products. In this study, we have determined nickel’s suppressive effect on TCDD-induced expression of CYP1A1 and CYP1A2, two members of the cytochrome P450 super-family. We have also analyzed CYP1A1 and CYP1A2 levels after expression of AhR with various lysine mutations. We have shown that induction of CYP1A1 and CYP1A2 by TCDD and other AhR ligands is significantly suppressed by hypoxia-mimetics including nickel. This effect is likely due to a competition for α-sub-unit shared by AhR and HIF-1 transcription factors. We have also found that substitutions of lysines 14, 17, and 21 with arginines suppress the ability of AhR to transactivate P450 genes after treatment with TCDD. Ligand-mediated AhR activation can be significantly modulated by co-exposure to other environmental toxicant (s) or by its lysine mutations.