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-tetrachlorodibenzo-p-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.

FIGURE 1

Transformation of the latent AhR tetramer to an activated transcriptional complex.

FIGURE 2

Proposed mechanisms of AhR/ARNT-mediated transcriptional regulation. (A) Ligand-activated AhR-ARNT heterodimers bind their cognate response element in the regulatory regions of their target genes, assemble coactivator machinery, and facilitate transcriptional activation. (B) In combination with other stimuli, transcription factor tethering (TF1) to AhR, including the combinatorial recruitment of other classes of transcription factors (TF2), or (C) AhR/ARNT tethering to transcription factors at their cognate response elements. (D) DNA bending allowing AhR/ARNT DRE-bound complexes to interact with other DNA-bound transcription factors.

FIGURE 3

Possible sites of AhR repression of inflammation-mediated transcription.