An introduction to the molecular basics of aryl hydrocarbon receptor biology

Abstract

Depending on their chemical structure and properties, environmental chemicals and other xenobiotics that enter the cell can affect cellular function by either nonselective binding to cellular macromolecules or by interference with cellular receptors, which would initiate a more defined cell biological response. One of these intracellular chemosensor molecules is the aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family that is known to mediate the biochemical and toxic effects of dioxins, polyaromatic hydrocarbons and related compounds. Numerous investigations have revealed that the AhR is not only a master regulator of drug metabolism activated by anthropogenic chemicals, but is also triggered by natural and endogenous ligands and can influence cell biological endpoints such as growth and differentiation. Cutting-edge research has identified new intriguing functions of the AhR, such as during proteasomal degradation of steroid hormone receptors, the cellular UVB stress response and the differentiation of certain T-cell subsets. In this review we provide both a survey of the fundamental basics of AhR biology and an insight into new functional aspects of AhR signaling to further stimulate research on this intriguing transcription factor at the interface between toxicology, cell biology and immunology.

Proteomic pathway analysis of the hippocampus in schizophrenia and bipolar affective disorder implicates 14-3-3 signaling, aryl hydrocarbon receptor signaling, and glucose metabolism: Potential roles in GABAergic interneuron pathology

“…AHR is a highly conserved transcription factor ubiquitously expressed in the brain, whose most potent ligand and activator is 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), a common industrial pollutant (Abel and Haarmann-Stemmann, 2010). Rodents exposed to TCDD during neurodevelopment exhibit deficits in working memory (Seo et al, 1999), delayed alternation tasks (Markowski et al, 2002), and emotional learning (Nishijo et al, 2007).…”

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

“…6 We have previously shown that UVB exposure of keratinocyte (KC) resulted in the activation of the aryl hydrocarbon receptor (AHR), 10 a ligand-activated transcription factor and central regulator of drug metabolism. 11 More precisely, UVB rays are absorbed by free tryptophan in the cytosol of KC, resulting in the formation of the tryptophan-photoproduct 6-formylindolo [3,2-b]carbazole (FICZ), 10 a high-affinity ligand of the AHR. 12 Alike polycyclic aromatic hydrocarbons (PAHs) and dioxins, FICZ binds to the AHR and initiates the dissociation of the cytosolic AHR multiprotein complex, consisting of heat-shock protein 90, tyrosine kinase c-src, and other co-chaperones, thereby enabling the nuclear translocation of AHR.…”

“…12 Alike polycyclic aromatic hydrocarbons (PAHs) and dioxins, FICZ binds to the AHR and initiates the dissociation of the cytosolic AHR multiprotein complex, consisting of heat-shock protein 90, tyrosine kinase c-src, and other co-chaperones, thereby enabling the nuclear translocation of AHR. 10,11 In the nucleus, the AHR dimerizes with ARNT (AHR nuclear translocator) and binds to xenobiotic-responsive elements (XRE) in the promoter region of genes to enforce their transcription. The AHR gene battery encodes for drug-metabolizing enzymes, such as cytochrome P450 (CYP) 1A1, as well as for proteins involved in the regulation of cell growth and differentiation.…”

“…The AHR gene battery encodes for drug-metabolizing enzymes, such as cytochrome P450 (CYP) 1A1, as well as for proteins involved in the regulation of cell growth and differentiation. 11,13 Beside this AHR/ARNT-triggered pathway, the ligand-driven release of c-src in the cytoplasm initiates so-called 'non-genomic' AHR signaling that sequentially comprises c-src translocation from cytosol to cell membrane, phosphorylation of the epidermal growth factor receptor, activation of downstream MAPK, and induction of another set of target genes, including cyclooxygenase-2 (COX-2). 10,13 As an induction of CYP activity can lead to ROS formation and the role of COX-2 in inflammation and cancer is well-known, the AHR is regarded as a crucial regulator of the UVB stress response.…”

The Impact of Pollution on Skin and Proper Efficacy Testing for Anti-Pollution Claims

“…Their binding will prevent the negative impact of AhR signaling in response to pollution. These AhR antagonist belongs mainly to polyphenol class such as flavonoids or catechins [36,37].…”