Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Aryl Hydrocarbon Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101571

Synonyms

Historical Background

Driven by a focus on public health, Dr. Alan Poland’s laboratory at the University of Rochester originally identified the aryl hydrocarbon receptor (AHR) in 1976 by using radiolabelled [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to ascertain its inner cellular binding protein (Poland et al. 1976). During the following 40 years, numerous endeavors have been devoted to elucidating its molecular and physiological significance, many of which have added and continue to enhance our knowledge of this transcription factor. Of particular note, two milestones should be mentioned that have significantly contributed to the characterization of the AHR protein (Gasiewica and Henry 2012): the identification of the Ah locus (Gielen et al. 1972; Nebert et al. 1972) and the report of the Ah b and Ah d alleles exhibiting high- and low-aryl hydrocarbon hydroxylase (AHH) activity in different mouse strains, respectively (Nebert et al. 1982). These findings were followed by the identification of a consensus DNA-binding site for the receptor that was originally termed the dioxin response element (DRE) (Denison et al. 1988a, b), eventually becoming the xenobiotic response element (XRE) (Fujisawa-Sehara et al. 1988). Within this element, the core recognition sequence responsible for guiding AHR to its genomic home was identified, termed AH response element (AHRE). In the late 1980s, the cloning and sequencing of both the AHR and ARNT (Ah receptor nuclear translocator) enabled researchers to classify the receptor as a member of the bHLH-PAS family of transcription factors based on the high-sequence homology (Burbach et al. 1992; Ema et al. 1992). Around the same time, the function of several AHR-interacting partners including heat shock protein 90 (HSP90), ARNT, and AIP (AHR interacting protein) were determined to regulate AHR intracellular stability, ligand-binding ability, and cytoplasmic-nuclear trafficking (Petrulis and Perdew 2002; Harper et al. 2006). Advances in molecular biology during the 1990s enabled the search for differentially expressed genes and facilitated the creation of AHR-knockout mice, opening a new chapter for the study of AHR’s role in both mediating xenotoxicity and normal physiology. The progress of technical innovation, especially the usage of cloning, sequencing, bioinformatics, biostatistics, transfection, and chromatin analyses has further enabled the discovery of genes directly responsive to the AHR and the interactions between signaling pathways associated with these genes. Recent research focusing on these interactions has broadened the perspective of AHR’s role as a xenometabolic mediator through the elucidation of diverse functions identifying AHR as a physiological regulator of processes involved in cell cycle, tissue differentiation, stem cells, immune system, and so on (Gasiewica and Henry 2012). Our understanding of the receptor has evolved from its original association with toxicity of a specific class of structurally related environmental pollutants into an ubiquitous transcription factor involved in important developmental processes (Gasiewica and Henry 2012).

AHR Evolution and Primary Structure

Evidence of AHR homologs in most major groups of modern bilaterian animals, cnidarians (Putnam et al. 2007), and placozoans (Srivastava et al. 2008) has led to the inference that the receptor is an ancient, conserved protein. These groups comprise the clade Eumetazoa, whose common ancestor can be traced back approximately 600 million years (Peterson and Butterfield 2005), suggesting that AHR is highly conserved in phylogeny from invertebrates to vertebrates and demonstrating that it may be involved in the regulation of certain xenobiotic-independent functions and physiological processes (Hahn 2002). Given the relevance to public health, most investigations have focused on mammalian AHR; therefore it may serve as an introduction for describing the protein’s structure as it pertains to function.

The human AHR gene encodes a protein of 848 amino acids and the murine ortholog encodes a protein of 805 amino acids (Abel and Haarmann-Stemmann 2010). Figure 1 shows a schematic structure of the murine AHR protein. The bHLH domain, responsible for DNA binding and protein dimerization (Gu et al. 2000), resides at the N-terminal region and consists of conserved amino acids that form two amphipathic α-helices connected through a relatively nonconserved loop and an adjacent region of basic amino acids (Abel and Haarmann-Stemmann 2010). The PAS domain, comprised of two subdomains PAS-A and PAS-B (Gu et al. 2000), is immediately adjacent to the bHLH domain and mediates several functions, serving as a docking site for protein-protein interactions, ligand binding (Schmidt et al. 1996), and housing the N-terminal nuclear localization signals (NLS) and nuclear export signals (NES) required for AHR activation (Ikuta et al. 1998). At the C-terminus, the AHR carries a large, glutamine-rich transactivation domain (TAD) that is indispensable for target gene activation due to its interactions with several transcription coactivators (Rowlands et al. 1996). Together, the bHLH, PAS, and TAD embody the conserved structure of the AHR, though species-specific adaptations which influence function exist.
Aryl Hydrocarbon Receptor, Fig. 1

The aryl hydrocarbon receptor is an evolutionarily conserved protein in vertebrates. AHR is a highly conserved protein found in nearly all vertebrates. The hierarchical view presents the degree of similarity for AHR between multiple species and was adapted from UniProt (The UniProt Consortium 2015). The annotated protein structure for the mouse is enlarged and annotated in further detail to better describe the regions responsible for mediating specific functions of AHR. The annotations in the mouse AHR were adapted from (Abel and Haarmann-Stemmann 2010) and originally published by (Fukunaga et al. 1995)

An amino acid sequence comparison between mouse and human AHR revealed ~85% sequence identity within the N-terminal half of the receptor. In contrast, the C-terminal half only exhibits 58% sequence identity, due in part to most nonconserved changes occurring within the TAD (Murray et al. 2014). Probably the most dramatic difference between human and mouse AHR is the distinct ligand binding affinity. For example, mouse AHR binds TCDD with a tenfold higher ligand affinity than its human ortholog, owing to a single amino acid residue difference in the middle of the ligand binding pocket (valine 381 in human AHR corresponding to alanine 375 in mouse AHR) (Ramadoss and Perdew 2004). Similarly, the decreased ligand binding affinity of the murine Ahr d allele compared to Ahr b is the result of a single amino acid substitution, from V375 in AHRb to A375 in AHRd (Chang et al. 1993; Ema et al. 1994; Poland et al. 1994).

Invertebrate AHR homologs were found in the nematode Caenorhabditis elegans (Powell-Coffman et al. 1998), fly Drosophila melanogaster (Duncan et al. 1998), chordate Ciona intestinalis (Dehal et al. 2002), and mollusks (Butler et al. 2001; Hahn et al. 2006). The C. elegans orthologs of AHR and ARNT, AHR-1 and AHA-1, are encoded by the ahr-1 (aryl hydrocarbon receptor-related) and aha-1 (ahr-1 associated) genes (Powell-Coffman et al. 1998). AHR-1 is translated as a 602 aa-length protein with an HLH domain at the N-terminal followed by PAS-A and PAS-B domains. The sequence of this protein shares similar N-terminal domain structures with the human ortholog, maintaining 38% identity over a region of 395 aa; however, minimal similarities beyond 400 residues are preserved (Powell-Coffman et al. 1998). Despite the sequence dissimilarity, the signaling network is fairly conserved; AHR-1 and AHA proteins interact with each other to form a complex that binds to specific DNA fragments containing the AHRE (5′-KNGCGTG) sequence (Powell-Coffman et al. 1998). AHR-1 can bind to HSP90 but not the XAP2 chaperone (Bell and Poland et al. 2000). Stark differences exist in the activation of ahr-1 as dioxin is not a recognized ligand and nuclear translocation of the receptor does not require an exogenous ligand (Powell-Coffman et al. 1998). Ahr-1 is predominantly expressed in neurons (Huang et al. 2004) and has been suggested to function as a regulator of neuronal differentiation, as mutations of its gene result in defective neuronal development, while ablation induces specific defects in neuronal differentiation such as aberrant cell migration and axon branching (Qin and Powell-Coffman 2004).

In the fruit fly D. melanogaster, the homologs of mammalian AHR and ARNT are encoded by the spineless (ss) and tango genes, respectively (Sonnenfeld et al. 1997; Duncan et al. 1998). The Drosophila ss gene encodes an 884 aa-length protein, SS, that shows extensive similarity to human and murine AHR as the organization of domains between the orthologs is highly similar. Comparing the Drosophila Spineless protein with mammalian AHR shows that there is 71% identity between the two proteins in the bHLH region, 45% identity in the PAS domain, and 41% identity overall (Duncan et al. 1998). Similar to C. elegans, the fly Spineless protein does not bind TCDD (Butler et al. 2001) and heterodimerization with the Tango protein occurs in the absence of a ligand (Emmons et al. 2007), allowing the complex to bind specific DNA elements (Emmons et al. 1999). Spineless is involved in neurite morphogenesis (Kim et al. 2006) and gene targeting results in the inappropriate arrangement of antennae and legs, suggesting a functional role in limb development (Emmons et al. 1999). Together, the common features of these studies identify AHR’s involvement in neuronal differentiation as well as downstream functions (Barouki et al. 2007) through the demonstration of its important physiological role during invertebrate development, suggesting that AHR is multifaceted in its functions.

In fish, there are at least two AHR genes, denoted as ahr1 and ahr2 (Hahn 2002; Hahn et al. 1997), which may be the result of a gene duplication event during early vertebrate evolution as suggested by phylogenetic comparisons (Hahn 2002). Zebrafish ahr1a and ahr2 cDNAs encode 805 aa- and 1027 aa-length proteins, respectively; sharing 40% amino acid identity overall and 58% in the N-terminal half. The zebrafish ahr1b gene encodes a 940 aa-length protein, sharing 34% identity with Ahr1a (Karchner et al. 2005). Zebrafish Ahr1a and human AHR share 43% aa identity overall and 65% in the N-terminal half (Andreasen et al. 2002). Ahr1 and Ahr2 share 40% amino acid identity overall. Linkage group mapping demonstrated that Ahr1 is the ortholog of the human AHR (Hahn 2001; Andreasen et al. 2002). Interestingly, cloning studies and expression analysis have suggested that Ahr2 seems to be the predominant form (Hahn 2002). Both of the receptors share common features specific to mammalian AHR including dioxin binding, interaction with ARNT and XAP2, AHRE binding, and transcriptional activation of target genes (Roy and Wirgin 1997; Abnet et al. 1999; Karchner et al. 1999; Hahn 2002); However, the two Ahrs expressed in fish have distinct features as well. For example, Ahr1 differs from Ahr2 in tissue-specific expression. Furthermore, Ahr1 lacks high-affinity binding of TCDD and a functional TAD, suggesting that Ahr1 may have different functions compared to Ahr2 (Andreasen et al. 2002).

The amphibian AHR has been studied in Xenopus laevis, one of the model animals commonly used in laboratories. X. laevis expresses two arnt (Bollerot et al. 2001; Rowatt et al. 2003), and two distinct ahr1 (Ohi et al. 2003; Lavine et al. 2005) genes, ahr1α and ahr1β; each share 86% amino acid identity, being orthologous to mammalian AHR and paralogous to the piscine Ahr2, respectively (Lavine et al. 2005). Both Ahr1α and Ahr1β exhibit TCDD-dependent binding to cognate DNA sequences, but they exhibit low TCDD-binding affinity (at least 20-fold lower affinity than the mouse AHRb protein) as well as low transactivation properties (Lavine et al. 2005).

In avian species, a single AHR isoform (corresponding to mammalian AHR) has been identified in the common tern (Sterna hirundo) (Karchner et al. 2006) and domestic chicken (Gallus gallus) (Walker et al. 2000), while two distinct orthologs, designated as AHR1 and AHR2, were identified in the black-footed albatross (Phalacrocorax nigripes) and common cormorant (Phalacrocorax carbo) (Yasui et al. 2004, 2007). Phylogenetic analysis suggests that avian AHR1 and AHR2 are orthologous to mammalian AHR and fish AHR2, respectively, with AHR1 appearing to be the dominant form of avian AHRs. cDNA cloned from the AHR of a chick embryo codes an 858 aa-length protein in which the bHLH domain exhibits 87–100% identity to avian, mammalian, and amphibian Ahr, while the PAS region is slightly less conserved with 97% identity to other avian sequences (Walker et al. 2000). To demonstrate the conservation of this protein, Walker et al. showed that chicken AHR is capable of heterodimerizing with human ARNT and subsequent binding to the mammalian DRE in a ligand-dependent manner. Though both proteins are transcriptionally active, AHR2 seems to have reduced transcriptional efficacy (Walker et al. 2000). Similar to human and mouse orthologs, avian AHRs are capable of binding ligands and exhibit dramatic differences in their sensitivities to polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs). For example, the tern AHR has a lower binding affinity and reduced ability to support TCDD-dependent transactivation (Karchner et al. 2006) in contrast to the domestic chicken, which is extremely sensitive to TCDD and other HAHs (Heid et al. 2001). Studies using site-directed mutagenesis demonstrated that the species-specific differences in sensitivity to HAHs results from two amino acid residues in the ligand-binding domain (Karchner et al. 2006).

AHR Ligands, Exposure, and Relevance to Human Health

In the years following the identification of the receptor, several research endeavors have been undertaken to identify the synthetic and natural ligands of AHR, as well as characterize the effects of exposure to these compounds. AHR ligands vary greatly in their chemical properties/structure and binding affinities, as reviewed in (Busbee et al. 2013). The synthetic ligands, including the HAHs and PAHs, are common components of environmental pollutants with tendencies to possess stronger affinities for the receptor. Notable examples of PAHs include benzo[a]pyrene (B[a]P), anthracene, and 3-methylcholanthrene (structures shown in Fig. 2). Representative members of HAHs include polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). Within these classifications, the conformations of PCBs encompass both coplanar and noncoplanar compounds consisting of two benzene rings, though only coplanar PCBs are believed to be AHR ligands capable of eliciting effects through the receptor. PCDDs and PCDFs consist of only coplanar compounds characterized by two benzene rings connected through an oxygenated ring. Generally speaking, HAHs have a higher binding affinity for the AHR (in the pM to nM range) in comparison to PAHs (in the high nM to μM range) (Busbee et al. 2013), with greater affinity for the receptor often indicating increased toxicity. Collectively, PCDFs, PCDDs, and PCBs are a group of chlorinated organic chemicals commonly termed “dioxin-like compounds (DLCs).” The HAHs within this group exhibiting the highest identified binding affinity to AHR is TCDD and has become the prototypical ligand used for studying the bioactivity of the AHR. In this review, it will be highlighted as an example of a synthetic AHR ligand with potent toxicities directly linked to human exposure.
Aryl Hydrocarbon Receptor, Fig. 2

The structural diversity of AHR-activating ligands. Several varied structures and classes of ligands have been shown to be capable of binding to and activating AHR. The best characterized ligand that has been studied is TCDD, which acts as the prototypical ligand for AHR and represents a broad class of compounds known as halogenated aromatic hydrocarbons (HAH) encompassing polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). Similarly, benzo[a]pyrene (B[a]P) is the prototypical ligand representing a class of compounds known as polycyclic aromatic hydrocarbons (PAHs). Several other classes of naturally occurring compounds important in the human diet have been found to act as AHR ligands, represented below by four commonly studied compounds

In humans, three main routes of exposure to TCDD exist: background exposure, industrial accidents, and occupational exposure (IPCS 1989; U.S. EPA 2007). People are globally exposed to background levels of TCDD from multiple sources that include air, water, soil, and the commercial food supply (U.S. EPA 2007), with dairy products, meat, and fish being specific examples of products containing trace amounts of TCDD (Svensson et al. 1991; Hansson et al. 1997; Bocio and Domingo 2005; Chan et al. 2013). According to studies conducted by the U.S. Environmental Protection Agency (EPA), background exposure corresponds to approximately 95% of average human exposure, demonstrated by the concentrations of DLCs in human tissues (U.S. EPA 2007). These studies showed that tissue levels of dioxin increase with age in a trend that appears fairly uniform geographically, racially, and sexually, suggesting bioaccumulation (U.S. EPA 2007). While not directly synthesized for a particular use, higher levels of human exposure to TCDD have been observed in multiple situations due to its synthesis as a byproduct of manufacturing processes, with notable examples including industrial accidents, chlorophenol/phenoxy herbicide production plants, and the use of Agent Orange during the Vietnam War. A particularly tragic example is the explosion that occurred in a chemical plant near the town of Seveso, Italy, in 1976, which resulted in the release of 1–5 kg of TCDD into the environment and elevated levels of exposure to a large population in the surrounding regions several fold higher than typical background concentrations (Signorini et al. 2000; Mocarelli 2001). Occupationally, workers in chlorophenol/phenoxy herbicide chemical plants are exposed to high levels of TCDD due to its synthesis as a byproduct (Kelada 1990; Ryan and Norstrom 1991; Hu et al. 2013). Similarly, heavy use of the contaminated defoliant Agent Orange during the Vietnam War exposed military personnel (Gough 1991; Dwyer and Flesch-Janys 1995). TCDD is extensively distributed throughout the body upon exposure followed by primary deposition in liver and adipose tissues (IPCS 1989; U.S. EPA 2007). The metabolism of this chemical is extremely slow with a half-life of 7–12 years, resulting in the persistence of TCDD within human tissues, particularly fatty tissues, for extended periods of time (IPCS 1989). The prevalence of daily exposure combined with the chemical’s persistence in the human body has characterized TCDD as a compound that poses potential risks to humans.

The potentially adverse effects in the general population may result from chronic exposure to low levels of TCDD. The concentration within the body gradually accumulates due to daily intake and absorption followed by low metabolism and excretion, commonly referred to as body burden; the total amount of dioxin uptake present in the body at any one time (IPCS 1989; U.S. EPA 2007). TCDD concentrations in human fat throughout the world are estimated to be in the range of 5–15 parts per trillion, or 2 pg/g body fat (Steenland et al. 2004; Pelclova et al. 2006). The immediate effects of TCDD body burden to the general population are not directly observable and remain controversial due to its ubiquitous presence in the environment. However, by comparing the effects produced by dioxin body burdens in experimental animals to those in humans, DeVito et al. suggested that some individuals exposed to dioxin may exhibit carcinogenic and noncarcinogenic effects at a concentration within one to two orders of magnitude for the body burdens in the general populations (DeVito et al. 1995). With respect to both source elimination and emission control, evidence shows decreased temporal trends in human TCDD body burden over the past three decades (Aylward and Hays 2002; U.S. EPA 2007).

TCDD was classified as a “human carcinogen” by the National Toxicology Program (NTP) and the International Agency for Research on Cancer (IARC) in 1997, based on limited evidence in humans and sufficient research conducted in experimental animals (IARC 1997; Steenland et al. 2004). The most unusual aspect of TCDD’s toxicity is that it affects multiple organs (Pelclova et al. 2006; Denison et al. 2011) with greatly varying responses that depend on several factors including cell type, tissue, age, sex, species, dose, and duration of exposure (Mandal 2005). Table 1 (Denison et al. 2011; Pohjanvirta et al. 2012) summarizes most of TCDD’s toxic effects observed in both humans and experimental animal models. However, some points need to be clarified when discussing TCDD toxicity. First, evidence of its toxic effects in humans mainly comes from studies of high-level, acute human exposure that were discussed previously. The estimated exposures within these groups vary widely but are significantly higher than current background levels, often by as much as 1,000-fold (Pelclova et al. 2006). Second, the sensitivity to TCDD toxicity varies greatly among species and therefore the doses used for animal studies varied significantly among different experiments. Finally, an array of evidence tends to suggest that the adverse effects of chronic exposure to dioxins are similar to those following acute exposure in both human and animal studies (Public Health England 2008).
Aryl Hydrocarbon Receptor, Table 1

Major TCDD toxic effects in multiple species (Adapted from Denison et al. 2011 and Pohjanvirta et al. 2012)

Impact

Description of the impact

Target cell/tissue or mechanisms

Species affected

Acute lethality

 

Pathogenesis not well understood

Guinea pig, rat, mouse

Carcinogenesis

Tumor promotion

Liver

Rat, mouse

Cardiotoxicity

Cardiovascular disease; hypertension; atherosclerosis; ischemic heart disease

Cardiomyocytes

Rat

Dermal toxicity

Chloracne

Keratinocytes and sebacdous glands

Human, monkey, rabbit, mouse

Developmental toxicity

Exposure during development

Hard palate and kidney; reproductive tissue and sexual behavior; glutamatergic neurons and learning; molar teeth; heart

Mouse, Rat; monkey;

Diabetes

 

Hyperinsulinemia and insulin resistance

Human

Endocrine disruption

Testosterone, thyroxine, insulin, corticosterone, ACTH, TSH, melatonin

Impeded testicular biosynthesis; accelerated hepatic metabolism; impaired pancreatic secretion diurnal phase-dependent modulation; accelerated extrahepatic metabolism

Rat, mouse

Hepatotoxicity

Hyperplasia; hypertrophy; mitochondrial dysfunction; pro-apoptotic effects; anti-apoptotic effects

Hepatocytes and bile ducts

Mouse, rat, rabbit

Immunotoxicity

Thymic involution; immune suppression; thymocyte and T-cell apoptosis; splenic atrophy

B and T cells, NK cells, dendritic cells, Thymus atrophy

Mouse, rat

Neurotoxicity

Headaches, weakness, muscular pains and peripheral neuropathy

 

Human

Porphyria

 

Inhibition of uroporphyrinogen decarboxylase

Mouse, rat, human

Reproductive toxicity

Testis lesions

Spermatozoa, Leydig cells, Sertoli cells

Rat, mouse, guinea pig, monkey

Teratogenesis

Cleft palate; hydronephrosis

 

mouse

Wasting syndrome

Significant reduction of body weight

Central regulation of body weight?

Rat, guinea pig, mouse

In contrast, the natural AHR ligands are less toxic but still able to elicit responses through the AHR pathway. The majority of natural AHR ligands are introduced into biological systems through oral consumption of foods and herbal medicines (Busbee et al. 2013). More recently, a wide variety of lower-affinity ligands have been identified from diverse sources (Denison et al. 2011) including many commercial and consumer products such as fruits, vegetables, and spices which have been shown to possess AHR activation potential (Jeuken et al. 2003; Zhao et al. 2013). These compounds can be classified into broad categories such as flavonoids, indoles, and tryptophan metabolites among others. The flavonoids are a large class of polyphenolic compounds that are present in the previously mentioned foods and, based on their structures, can be divided into flavonols, flavanols, flavans, flavanones, and isoflavones. Tryptophan, one of the 20 basic amino acids, is a building block for protein synthesis but also functions as a biochemical precursor for the neurotransmitter serotonin, niacin (vitamin B3), and the phytohormone auxin. Metabolites of tryptophan that are capable of activating AHR include indigo, indoles, etc. (Busbee et al. 2013). Most of these nonclassical AHR ligands are relatively low-affinity ligands and only moderate inducers of AHR-dependent gene expression compared to TCDD. However, 6-formylindolo[3,2-b]carbazole (FICZ), a photoproduct of tryptophan, is an example of a natural ligand with exceptional affinity to the receptor, binding to AHR with even greater affinity than TCDD (Rannug et al. 1987, 1995). Coupled with species-specific differences in ligand affinity, the identification of these strikingly diverse ligand structures suggests that the AHR has an extremely promiscuous ligand-binding site that may be tailored to the particular functions of the receptor in each species (DeGroot et al. 2012).

The AHR Signaling Pathway

TCDD is the prototypical ligand for AHR with most, if not all, biological effects being mediated by AHR; an absolute requirement for the adverse outcomes of TCDD exposure that have been discussed in the previous section. At the heart of these toxicological effects is the AHR signal transduction pathway (Fig. 3). In the absence of an activating ligand, AHR exists as a cytosolic protein in a complex containing two molecules of the 90 kD HSP90, one molecule of the HSP90-associated cochaperone p23 and one molecule of the immunophilin homolog hepatitis B virus X-associated protein XAP2 (also termed AIP (AHR-interacting protein) or ARA9 (AHR-associated protein 9)) (Denis et al. 1988; Nair et al. 1996; Ma and Whitlock 1997; Beischlag et al. 2008). Within the AHR complex, HSP90 binds to both the ligand-binding (PAS) domain and the bHLH DNA-binding domain of the receptor (Perdew and Bradfield 1996). The binding interactions of HSP90 assist in proper folding and enhanced stability of the receptor (Antonsson et al. 1995) while masking the NLS of AHR (Fujii-Kuriyama and Kawajiri et al. 2010). The receptor is further stabilized through the association of XAP2 protein, preventing dynamic nucleo-cytoplasmic shuttling of the receptor in the absence of an activating ligand (Pollenz et al. 2006). Little is known about the significance of ligand-independent AHR shuttling; however, one hypothesis is that the AHR may have some functions in the nucleus through interactions with other proteins (Ramadoss and Perdew 2005).
Aryl Hydrocarbon Receptor, Fig. 3

The signaling pathways of AHR. The early findings of AHR’s involvement in cell signaling led to the elucidation of the (1) “Canonical” pathway that describes its ligand activation, translocation to the nucleus, heterodimerization with ARNT, and subsequent transcription factor activity. Recent years have identified several other mechanisms through which AHR can affect signaling including (2) heterodimerization with other cofactors and binding to noncanonical XREs, (3) integrating into transcription factor complexes where it does not directly bind DNA, and (4) interactions with other signaling pathways such as WNT and steroid hormone signaling through the formation of a CUL4B-based E3-ligase complex

Binding TCDD or another activating ligand causes the entire AHR complex to translocate into the nucleus where the receptor dissociates from its cytosolic complex, heterodimerizes with its partner ARNT (also termed HIF1β) (Reyes et al. 1992), and subsequently binds to the AHR (or dioxin) response element (AHRE) core consensus 5′-T/NGCGTG-3′ located in the promoters of AHR target genes (such as xenobiotic metabolizing enzyme CYP1A1 and other AHR-dependent responsive genes) (Denison et al. 1988a; Swanson et al. 1995). The binding of the AHR:ARNT heterodimer to an AHRE motif results in DNA bending and forms the scaffold for multiple coactivator complexes associated with the receptor (Elferink and Whitlock 1990). These complexes may include chromatin remodeling proteins (i.e., BRG-1 p160), mediators (i.e., TRAP-DRIP), and/or several established coactivators such as p160, p300/CPB, RIP140, TRIP230, etc. (Hankinson 2005). The assembly of AHR with transcription coactivators at the AHRE may facilitate the initiation of gene transcription, with the most notable example being the detoxification gene Cyp1a1. Increasing evidence indicates that in addition to the well-known xenobiotic metabolism genes in the Cyp1 family of cytochromes P450, there are other AHR transcriptional targets including genes involved in cell cycle regulation and morphogenetic processes that may play a vital function during embryonic development (Sartor et al. 2009). After modulating transcription, AHR is then targeted for proteosomal degradation by polyubiquitination, attenuating the xenometabolic response (Mitchell and Elferink 2009). The induction of detoxification genes immediately after AHR:ARNT binding to the AHRE with recruitment of coactivators is widely accepted as canonical AHR signaling; however, evidence is growing for other mechanisms involving AHR-mediated processes. For instance, nonconsensus xenobiotic response elements (NC-XRE) have been identified that appear to confer direct AHR-DNA binding which does not seem to require the presence of ARNT. Huang et al. reported a NC-XRE in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene which recruits a novel protein-DNA complex responsible for TCDD inducible expression (Huang and Elferink 2012). The binding of the receptor to the NC-XRE is dependent on its interaction with Kruppel-like factor 6 (KLF6) (Wilson et al. 2013). Furthermore, Vogel et al. reported an interaction between RelB (an NF-κB subunit) and the AHR that may modulate IL-8 gene expression through a new RelBAHRE cis-element (Vogel et al. 2007a, b). Our group has reported that AHR participates in transcriptional activation at NC-XRE sites through indirect DNA binding, facilitated by the formation of a quaternary repressor complex with pRb, E2F, and DP1, the E2F-binding partner in transactivation of S-phase genes (Puga et al. 2000; Marlowe et al. 2004). Additionally, AHR-mediated ubiquitin ligase activity was found when investigating the crosstalk between AHR and sex hormone receptors, with AHR promoting polyubiquitination and subsequent 26S proteosomal degradation of steroid receptors (Ohtake et al. 2007) after the ligand-activated AHR assembles a CUL4B-based atypical E3 ubiquitin ligase complex to mediate nongenomic signaling pathways. The estrogen and androgen receptors were reported as substrates for this E3 ubiquitin ligase activity (Brunnberg et al. 2012; Ohtake and Kato 2012), which is believed to be one method for AHR’s ability to crosstalk with steroid receptor pathways. Recently, β-catenin, a transcription factor active in the WNT signaling pathway, was also found to be ubiquitinated by activated AHR (Kawajiri et al. 2009). Taken together, these interactions not only provide mechanistic insights into how the receptor crosstalks with crucial developmental pathways but may also help to elucidate the toxic effects associated with environmental pollutants capable of activating AHR.

Summary

Originally identified as a binding protein for a specific class of structurally related pollutants, AHR has been recognized as a ligand-activated transcription factor and a member of bHLH-PAS superfamily responsible for mediating the xenometabolic response (Mitchell and Elferink 2009; Gasiewica and Henry 2012). The receptor can be activated by structurally diverse ligands, both synthetic and natural, resulting in its translocation to the nucleus and subsequent regulation of metabolism-related gene transcription. This protective role of the AHR-mediated xenometabolic response is double-edged as ligand-induced activation, particularly by TCDD or B[a]P, results in tissue- and species-specific toxicities that have been demonstrated in numerous studies. Of particular note, recent studies have demonstrated that modifying the AHR signaling by some natural ligands may have therapeutic potential against inflammatory disorders (Busbee et al. 2013). Beyond mediating the toxicity of synthetic ligands, the study of AHR through an evolutionary perspective has found it to be highly conserved. Homologs have been identified from multiple species including, but not limited to, C. elegans, Drosophila, D. rerio, avians, and mammals, with recent studies demonstrating that the receptor serves important physiological functions during development. The study of AHR has evolved significantly over the years and, in light of recent findings, requires continued research to elucidate answers for questions surrounding its roles in normal development, homeostatic processes, and to concurrently integrate these findings with environmental factors to better understand the impact of pollutants on human health and diseases.

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Authors and Affiliations

  1. 1.Department of Cell, Developmental and Integrative BiologyUniversity of AlabamaBirminghamUSA
  2. 2.University of CincinnatiCincinnatiUSA