The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways

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.

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non–Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling

“…The identification of kynurenine (Kyn) as an endogenous AhR ligand was a major impetus for in-depth investigation of AhR's previously unknown function in physiologic and pathologic events (10). Although recent studies have suggested a potential role of AhR in regulating cell proliferation, cell-cycle distribution, and cell apoptosis, the underlying mechanism is largely unknown (11).…”

Down-Regulation of CYP1A1 Expression in Breast Cancer

“…The transcriptional activation of the CYP1A1 gene is mediated by the binding of environmental pollutants (benzo[a] pyrene) to the cytosolic receptor ,aryl hydrocarbon receptor (AhR) and then translocates to the nucleus where it heterodimerizes with another protein aryl hydrocarbon nuclear tranlocator (ARNT). This heterodimer binds to consensus regulatory sequences termed as aryl hydrocarbon response elements (AhREs) located in the promoter region of AhR target genes such as CYP1A1 and CYP1A2 and initiate their transcription by recruiting RNA polymerase II (Puga et al, 2009). In addition to the well known positive regulation of CYP1A1, the expression of this gene is repressed by several agents and conditions.…”

Activation of the aryl hydrocarbon receptor pathway may ameliorate dextran sodium sulfate‐induced colitis in mice

“…1 Aryl hydrocarbon receptor was first discovered as a mediator of dioxin toxicity, but, at present, the AhR pathway is thought to have diverse roles in many cellular functions including the immune system. 2,3 The AhR pathway has been recently shown to be an important regulator of inflammation and immunity. 4,5 For instance, Ahr has an essential role in the negative regulation of the lipopolysaccharide (LPS) signaling pathway through interaction with Stat1.…”