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Abstract

Exposure to toxic polycyclic aromatic hydrocarbons raises a number of toxic and carcinogenic responses in experimental animals and humans mediated for the most part by the aryl hydrocarbon -- or dioxin -- receptor (AHR). The AHR is a ligand-activated transcription factor whose central role in the induction of drug-metabolizing enzymes has long been recognized. For quite some time now, it has become clear that the AHR also functions in pathways outside of its role in detoxification and that perturbation of these pathways by xenobiotic ligands may be an important part of the toxicity of these compounds. AHR activation by some of its ligands participates among others in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, immediate-early gene induction, cross-talk within the RB/E2F axis and mobilization of crucial calcium stores. Ultimately, the effect of a particular AHR ligand may depend as much on the adaptive interactions that it established with pathways and proteins expressed in a specific cell or tissue as on the toxic responses that it raises.

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Figures

Figure 1
Figure 1. AHR Signaling
Shown are the key events in signaling through the Ah receptor. Entry of ligand (TCDD in the figure) through the cell membrane leads to binding to the receptor followed by translocation of the cytosolic heat-shock chaperone complex to the nucleus. Various MAP kinases are involved in this step. Once in the nucleus, the AHR dissociates from the heat-shock complex, and forms a complex with ARNT that recruits p300 and binds to the cognate sites in DNA. Probably through a DNA-looping step, the complex recruits the basal transcription factors and RNA pol II needed for initiation of transcription. Not shown in the scheme is the obligatory removal of a HDAC1-DNMT1 complex bound in the proximity of the TATA box that blocks RNA pol II recruitment and effectively maintains the gene in a silent state.

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