Regulation of constitutive and inducible AHR signaling: Complex interactions involving the AHR repressor

Abstract

The AHR is well known for regulating responses to an array of environmental chemicals. A growing body of evidence supports the hypothesis that the AHR also plays perhaps an even more important role in modulating critical aspects of cell function including cell growth, death, and migration. As these and other important AHR activities continue to be elucidated, it becomes apparent that attention now must be directed towards the mechanisms through which the AHR itself is regulated. Here, we review what is known of and what biological outcomes have been attributed to the AHR repressor (AHRR), an evolutionarily conserved bHLH-PAS protein that inhibits both xenobiotic-induced and constitutively active AHR transcriptional activity in multiple species. We discuss the structure and evolution of the AHRR and the dominant paradigm of a xenobiotic-inducible negative feedback loop comprised of AHR-mediated transcriptional up-regulation of AHRR and the subsequent AHRRmediated suppression of AHR activity. We highlight the role of the AHRR in limiting AHR activity in the absence of xenobiotic AHR ligands and the important contribution of constitutively repressive AHRR to cancer biology. In this context, we also suggest a new hypothesis proposing that, under some circumstances, constitutively active AHR may repress AHRR transcription, resulting in unbridled AHR activity. We also review the predominant hypotheses on the molecular mechanisms through which AHRR inhibits AHR as well as novel mechanisms through which the AHRR may exert AHR-independent effects. Collectively, this discussion emphasizes the importance of this understudied bHLH-PAS protein in tissue development, normal cell biology, xenobiotic responsiveness, and AHR-regulated malignancy.

Molecular Signature of Smoking in Human Lung Tissues

“…The gene most strongly upregulated by smoking was the aryl hydrocarbon receptor repressor (AHRR), which is a negative regulator of the aryl hydrocarbon receptor (AHR) signaling pathway (32,33). This pathway, also known as the xenobiotic or dioxin-signaling pathway, is an important regulator of cellular responses to exogenous ligands.…”

The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation

“…To test this hypothesis, we evaluated the effects of AhR inhibition using ectopic expression of an AhR reporter plasmid previously shown to block human AhR transcriptional activity. 42,43 We constructed and used a lentiviral vector that encoded an AhR repressor (AhRR) element, along with a ZsGreen reporter ( Figure 6A). This AhRR element potently and specifically inhibits either baseline or AhR agonistinduced AhR transcriptional activity.…”

“…This AhRR element potently and specifically inhibits either baseline or AhR agonistinduced AhR transcriptional activity. 42,43 In contrast to cells transduced with a control ZsGreen reporter, cells infected with the AhRR-ZsGreen lentivirus and cultured for 5 days produce a significantly higher number of large, CD41…”

MicroRNA transcriptome analysis on hypertrophy of ligamentum flavum in patients with lumbar spinal stenosis

“…Ligand-evoked AHR signaling modulates inflammation and is possibly associated with atherosclerosis development 26,27) . In addition, ligandindependent action of AHR signaling has also been demonstrated, and thus the regulatory function of AHR signaling is widespread in various biological and pathological conditions 28,29) . Ahr knockout mice exhibited liver fibrosis and ligand-independent down-regulation of TGFβ1 expression is thought to be involved in the pathogenesis 30,31) .…”