ReviewPost screenThe AhR twist: ligand-dependent AhR signaling and pharmaco-toxicological implications
Highlights
► The AhR is a transcription factor activated by diverse exogenous compounds. ► The AhR regulates the expression of xenobiotic metabolism genes. ► KO models have revealed that the AhR also regulates endogenous processes. ► AhR modulators might be used as anti-tumorigenic or anti-inflammatory drugs. ► The AhR also regulates the proliferation of hematopoietic stem cells.
Section snippets
Endogenous functions and ligands of the AhR
The commonly accepted model of aryl hydrocarbon receptor (AhR) activation has been described in several reviews (Fig. 1) [1]. This model can be summarized, briefly, as follows: in the cytosol AhR is associated with chaperones. When a ligand binds to the receptor, the complex translocates into the nucleus and dissociates. In the nucleus heterodimerization with its partner AhR nuclear translocator (ARNT) occurs. This heterodimer binds to specific responsive elements called xenobiotic responsive
The XRE track
The first relevant study in this area concerned the pro-apoptotic protein Bax, which is induced by 7,12-dimethylbenz[a]anthracene (DMBA) – a polycyclic aromatic hydrocarbon (PAH) – in mouse oocytes [19]. This regulation largely explains oocyte death upon PAH treatment. The authors show that the AhR is central to this induction, but surprisingly TCDD had no effect. Analysis of the promoter led to the identification of a TCDD-unresponsive XRE, which was defined as an unusual responsive element (
Interaction with the estrogen receptor alpha pathway
Several AhR ligands have been shown to display endocrine-disrupting activities. One of the main interacting partners of the AhR is the estrogen receptor alpha (ERα). Under certain experimental conditions, it has been shown that treatment with dioxin can decrease the incidence of mammary tumors in Sprague Dawley rats [24]. The AhR has been reported to inhibit ERα activity through a variety of mechanisms. Indeed, dioxin induces the expression of target genes such as CYP1A1 and CYP1B1, which are
AhR ligands as potential pharmacological tools (Fig. 2)
Recent studies in several areas have suggested clearly that the pharmacological modulation of AhR activity will be important in the near future. For example, SAhRMs have been developed as new antitumorigenic agents, but have been shown to be relevant for application in fields other than cancer. Dioxins and the AhR have been linked to the control of inflammatory processes with interactions between the AhR and NF-κB factors which seem to be key mechanisms 48, 49, 50. Patel et al. have
Concluding remarks: the AhR(t) of plasticity
Recent studies using multiple models have clearly suggested that the functions of the AhR are more diverse than previously thought. Interestingly, the effects of ligands on signaling pathways seem to be highly plastic with associated responses that cannot be classified using the simple agonist/antagonist pharmacological alternatives. The nature of the ligand and the way it binds to the receptor seem to determine the nature of the targeted XRE and the related transcriptional responses. For
Acknowledgement
We warmly thank Dr Lawrence Aggerbeck for his crucial reading of this manuscript.
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Authors contributed equally to this work.