The Aryl Hydrocarbon Receptor Complex and the Control of Gene Expression

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that controls the expression of a diverse set of genes. The toxicity of the potent AhR ligand 2,3,7,8-tetrachlorodibenzop-dioxin is almost exclusively mediated through this receptor. However, the key alterations in gene expression that mediate toxicity are poorly understood. It has been established through characterization of AhR-null mice that the AhR has a required physiological function, yet how endogenous mediators regulate this orphan receptor remains to be established. A picture as to how the AhR/ARNT heterodimer actually mediates gene transcription is starting to emerge. The AhR/ ARNT complex can alter transcription both by binding to its cognate response element and through tethering to other transcription factors. In addition, many of the coregulatory proteins necessary for AhR-mediated transcription have been identified. Cross talk between the estrogen receptor and the AhR at the promoter of target genes appears to be an important mode of regulation. Inflammatory signaling pathways and the AhR also appear to be another important site of cross talk at the level of transcription. A major focus of this review is to highlight experimental efforts to characterize nonclassical mechanisms of AhR-mediated modulation of gene transcription.

Hepatic gene expression in flounder chronically exposed to multiply polluted estuarine sediment: Absence of classical exposure ‘biomarker’ signals and induction of inflammatory, innate immune and apoptotic pathways

“…Importantly, it was clear that the expected genes, CYP1A, UGT1B for BAP and vitellogenin, choriogenin for E2 were highly elevated (Fig 4). In addition glutathione reductase and GSTA showed very similar treatment-response profiles to CYP1A, indicating that in flounder these genes are likely to be regulated by the same mechanism as CYP1A, by the aryl hydrocarbon receptor (Beischlag et al, 2008). This demonstrates that although these genes were not induced by sediment exposure at environmentally relevant concentrations, the systems which regulate them in response to contaminants were intact in the isolated hepatocytes.…”

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

“…Ligand affinity is not the only factor that controls sensitivity, however. There are several other “control points” in the AHR signaling cascade that can influence the sensitivity to or magnitude of response (Beischlag, Luis Morales, Hollingshead, & Perdew, 2008; Hahn, 1998b). Similarly, the AHR is not the only factor that influences sensitivity to effects of DLCs; the expression and function of other members of the AHR pathway, including ARNT (Nukaya, Walisser, et al., 2010; Tomita, Sinal, Yim, & Gonzalez, 2000; Walisser et al., 2004) and AIP (Nukaya, Lin, et al., 2010), also are important.…”

Polycyclic Aromatic Hydrocarbons (PAHs) Mediate Transcriptional Activation of the ATP Binding Cassette Transporter ABCB6 Gene via the Aryl Hydrocarbon Receptor (AhR)

“…However, upon binding the ligand, AhR translocates from the cytoplasm to the nucleus, where it interacts with specific DNA response elements in target gene pro- moters and activates gene transcription (43,44). Thus in these studies, we first confirmed that B[a]P treatment results in the redistribution of AhR from the cytoplasm to the nucleus (supplemental Fig.…”