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    • Interaction between AhR and ligands leads to

    2024-02-21

    Interaction between AhR and ligands leads to AhR transformation (Fig. 1), characterized by a rapid receptor nuclear translocation and the formation of AhR/Arnt complex and the release of the chaperone proteins. Following AhR transformation, the AhR/Arnt complex binds to its cognate DNA consensus sequence (TNGCGTG) known as the xenobiotic response element (XRE) and regulates gene transcription. In attempts to identify global AhR target genes following ligand activation, microarray and ChIP-seq based experiments have been performed with different combinations of ligands and cell types [8], [11], [12]. Time course experiments were also used to study the temporal expression patterns of AhR target genes following AhR activation [13]. Although these large scale gene profiling experiments provide valuable information toward understanding the biological functions of AhR, especially during adaptive xenobiotic responses, results from these experiments were quite variable, and in general show few consensus genes. This is further complicated by the fact that experiments comparing AhR targets from propionitrile of different species or even between cell lines of the same species yielded very different results, with little overlap between target genes. Thus, the spectrum of genes regulated by AhR is thought to be strongly dependent on the chemical properties of the ligand as well as the identity and the developmental stage of the cells. Finally, a non-conventional, Arnt independent XRE has also been reported recently [14]. Despite the variability observed among AhR target gene discovery experiments, a small subset of AhR target genes including Cyp1a1 (cytochrome P450 1 family, member a1), Cyp1a2, Cyp1b1, Nqo1 (NAD(P)H quinone oxidoreductase 1), Aldh3a1 (aldehyde dehydrogenase 3 family, member a1), Ugt1a6 (UDP glucuronosyltransferase 1 family, polypeptide A6), and GST-Ya (glutathione S-transferase), collectively referred to as “AhR gene battery”, are commonly upregulated following AhR activation. These genes encode phase I and phase II xenobiotic metabolizing enzymes, which function to metabolize activating compounds and thus provide a vital role in the detoxification of xenobiotics.
    Regulation of AhR Environmental toxins such as TCDD and related HAHs have long been known to elicit a broad spectrum of toxicological endpoints, including severe wasting syndrome, teratogenicity, hepatotoxicity, neurotoxicity, immunotoxicity, and oncogenesis [15]. TCDD mediated toxicity is almost exclusively AhR dependent, as mice expressing low affinity AhR alleles are partially resistant to TCDD, and AhR null mice or mice with a knock in NLS mutant of the AhR are completely resistant to TCDD toxicity [16], [17], [18], [19], [20]. Conversely, transgenic mice expressing a constitutively active form of AhR have reduced life span, with increased incidence of developing stomach and liver tumors [21], [22]. Thus, it is crucial to maintain an adequate level of AhR for healthy cell physiology. To this end, cells have evolved a number of negative feedback systems to dampen down the excessive AhR signaling following activation (Fig. 1). Being a signal (i.e. ligand) regulated transcription factor, the most direct way of terminating AhR signaling is to withdraw the propionitrile upstream activating signal. Activation of AhR upregulates phase I and phase II xenobiotic metabolizing enzymes, which oxidize and derivatize PAH ligands, facilitating their removal by ATP dependent membrane transporters (Fig. 1) [23]. In addition, the cellular pool of AhR is also reduced by proteasome degradation (Fig. 1) [24], [25], [26]. Furthermore, the activity of AhR is also modulated by the nuclear export sequences of AhR (Fig. 1). Two independent NES motifs have been identified, located either within the bHLH region (N-NES) or in the PAS region (C-NES) of AhR. It has been suggested that the C-NES is involved in the maintenance of cytosolic AhR complex independent of AhR ligand, whereas the N-NES is required for the nuclear export of ligand activated AhR [27]. Consistent with this notion, Ikuta and colleagues showed that nuclear translocation of “endogenous” signal activated AhR in subconfluent keratinocyte HaCaT cells depends on a single serine residue (i.e. Ser68) at N-NES, and phosphorylation of Ser68 prevents CRM1 (chromosome region maintenance) mediated nuclear export of AhR [28].