The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways
Introduction
The aryl hydrocarbon (dioxin) receptor (AHR) is a cytosolic ligand-activated transcription factor that mediates many toxic and carcinogenic effects in animals and possibly in humans [1], [2]. It is generally accepted that its activation in vertebrates causes the toxic and carcinogenic effects of a wide variety of environmental contaminants such as dioxin (TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin), coplanar polychlorinated biphenyls (PCBs) and polycyclic or halogenated aromatic hydrocarbons (PAHs or HAHs). As a consequence of AHR activation, many detoxification genes are transcriptionally induced, including those coding for the Phase I xenobiotic-metabolizing cytochrome P450 enzymes CYP1A1, CYP1A2, CYP1B1, and CYP2S1, and the phase II enzymes UDP-glucuronosyl transferase UGT1A6, NAD(P)H-dependent quinone oxydoreductase-1 NQO1, the aldehyde dehydrogenase ALDH3A1, and several glutathione-S-transferases. AHR is a member of the bHLH/PAS family of heterodimeric transcriptional regulators (basic-region helix-loop-helix/Period [PER]-Aryl hydrocarbon receptor nuclear translocator [ARNT]-single minded [SIM]) [3], [4] involved in regulation of development [5] and in control of circadian rhythm, neurogenesis, metabolism and stress response to hypoxia. Evidence from AHR knockout mice, however, points to functions of the receptor beyond xenobiotic metabolism at several physiologic roles that may contribute to the toxic response. Ablation of the Ahr gene in mice leads to cardiovascular disease, hepatic fibrosis, reduced liver size, spleen T-cell deficiency, dermal fibrosis, liver retinoid accumulation and shortening of life span (reviewed in [6]), suggesting that it has biological functions other than xenobiotic detoxification that likely contribute to the overall toxic response resulting from its activation.
The AHR is widely expressed in practically all mouse tissues [7], and in humans expression is high in lung, thymus, kidney and liver. In the absence of ligand, the AHR exists as part of a cytosolic protein complex containing two HSP90 chaperone molecules, the HSP90-interacting protein p23 and the immunophilin-like protein XAP2 (also AIP or ARA9) [8], [9], [10]. Activation by ligand is followed by translocation of the complex into the nucleus, dissociation from the chaperone proteins and heterodimerization with ARNT. This AHR-ARNT heterodimer interacts with several histone acetyltransferases and chromatin remodeling factors [11], [12], [13], [14], [15], and the resulting complex binds to consensus regulatory sequences termed AhREs (aryl hydrocarbon response elements; also XREs or DREs), located in the promoters of target genes, and by mechanisms not yet well characterized, recruits RNA polymerase II to initiate transcription. The activated AHR is quickly exported to the cytosol where it is degraded by the 26S proteasome [16], hence preventing constitutive receptor activity.
Activation of the AHR by high-affinity HAH or PAH ligands results in a wide range of cell cycle perturbations, including G0/G1 and G2/M arrest, diminished capacity for DNA replication, and inhibition of cell proliferation. These alternative functions of the AHR are often accomplished in the absence of an exogenous ligand, but the underlying molecular mechanisms governing these processes remain elusive in part because no definitive endogenous ligands have been identified (reviewed in [17]). At present, all available evidence indicates that the AHR can trigger signal transduction pathways involved in proliferation, differentiation or apoptosis by mechanisms dependent on xenobiotic ligands or on endogenous activities that may be ligand mediated or completely ligand independent. These functions of the AHR coexist with its well-characterized toxicological functions involving the induction of Phase I and Phase II genes for the detoxification of foreign compounds.
In this review, we will address novel experimental evidence relating to these less orthodox AHR functions, focusing on new data appearing since our previous review of this subject [17] dealing with the role of the AHR in the activation of mitogen-activated protein kinases, cell cycle regulation, apoptosis and cell differentiation, with a focus on the cross-talk between AHR signaling pathways and the effectors, regulatory events and cell cycle checkpoints responsible for normal cellular functions. Key steps in the activation of AHR signaling are schematically shown in Fig. 1.
Section snippets
Cross-talk between cellular kinases and the Ah receptor
Post-translation modifications such as phosphorylation play a major role in the regulation of gene expression and function in eukaryotic cells. These covalent modifications control intracellular distribution, transcriptional activity and stability of growth factors, hormone receptors and transcription factors, including the AHR, and the physiologic activity of a number of genes too large to be discussed within the confines of this chapter (see [18] for a recent review covering this subject). In
Cross-talk of mitogen-activated protein kinases with the Ah receptor
The three families of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal/stress-activated protein kinases (JNK/SAPK), and the p38s are important intracellular signal transduction mediators. They control gene expression and various other events in eukaryotic cells through the phosphorylation of transcription factors and the modulation of their function. MAPKs can phosphorylate a large panel of substrates on serine and threonine residues
Cell cycle progression
The cell cycle results from a recurring sequence of molecular events that leads to the duplication of the DNA content of a cell and to the subsequent division of that cell. The cell cycle consists of five distinct phases: G0, G1, S, G2 and M. In G0, cells are in a state of quiescence in which they have temporarily or reversibly stopped dividing. In response to growth factors and mitogens, cells come out of quiescence into the G1 phase, during which cyclins and cyclin-dependent kinases (CDKs)
Conclusions
It might be premature to speculate on the connections between the different signal transduction pathways that cross-talk with the AHR and their possible role in adult disease, although it is an inescapable conclusion that those connections exist. In this context, it is obvious that AHR ligand-mediated repression of previously active genes that might have little connection with detoxification pathways, and concomitant induction of previously silent genes, are equally likely to derail cellular
Acknowledgment
The research in the authors’ lab described here is supported by NIEHS grants 2R01 ES06273, 2R01 ES10708 and P30 ES06096.
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Present address: Novartis Pharma AG, CH-4132 Muttenz, Switzerland.