The aryl hydrocarbon receptor repressor – More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer

Abstract

The aryl hydrocarbon receptor repressor (AhRR) was first described as a specific competitive repressor of aryl hydrocarbon receptor (AhR) activity based on its ability to dimerize with the AhR nuclear translocator (ARNT) and through direct competition of AhR/ARNT and AhRR/ARNT complexes for binding to dioxin-responsive elements (DREs). Like AhR, AhRR belongs to the basic Helix-Loop-Helix/Per-ARNT-Sim (bHLH/PAS) protein family but lacks functional ligand-binding and transactivation domains. Transient transfection experiments with ARNT and AhRR mutants examining the inhibitory mechanism of AhRR suggested a more complex mechanism than the simple mechanism of negative feedback through sequestration of ARNT to regulate AhR signaling. Recently, AhRR has been shown to act as a tumor suppressor gene in several types of cancer cells. Furthermore, epidemiological studies have found epigenetic changes and silencing of AhRR associated with exposure to cigarette smoke and cancer development. Additional studies from our laboratories have demonstrated that AhRR represses other signaling pathways including NF-κB and is capable of regulating inflammatory responses. A better understanding of the regulatory mechanisms of AhRR in AhR signaling and adverse outcome pathways leading to deregulated inflammatory responses contributing to tumor promotion and other adverse health effects is expected from future studies. This review article summarizes the characteristics of AhRR as an inhibitor of AhR activity and highlights more recent findings pointing out the role of AhRR in inflammation and tumorigenesis.

The increase of interfollicular epidermal stem cells and regulation of aryl hydrocarbon receptor and its repressors in the skin through hydroporation with anti‐aging cocktail

“…AhRR is known to negatively regulate AhR signaling via its inhibitory transactivation . Moreover, AhRR have anti‐inflammatory activity associated with tumor suppressive …”

“…In the skin, most of the cell types in the epidermis, as well as fibroblasts in the dermis, and immune cells are known to express AhR and AhRR. 8,9 In this study, AhR and AhRR expressions in the epidermis was evaluated because epidermis is directly exposed to the environment. Furthermore, the number of fibroblasts and immune cells are relatively small and variable.…”

ARNT/HIF‐1β links high‐risk 1q21 gain and microenvironmental hypoxia to drug resistance and poor prognosis in multiple myeloma

“…In the former, the role of the HIF‐1 complex consisting of HIF‐1α or ‐2α, a transactivating subunit that is inducible (eg, in response to hypoxia), and HIF1β, a regulatory subunit that is often considered as constitutively expressed and unaffected by hypoxia, has been well documented in tumor progression,11 tumor‐stroma interaction,12 metastasis,10 etc. In the latter, the AhR/ARNT complex binds to dioxin‐responsive elements (DREs) to induce transcription of target genes that encode drug‐metabolizing enzymes (eg, cytochrome P450 1A1) as well as proteins governing cell proliferation, differentiation, and apoptosis, which most likely facilitates carcinogenesis and tumor promotion 16. However, ARNT also forms a complex with AhR repressor (AhRR), which directly competes AhR/ARNT for binding to DREs and thus acts as a tumor suppressor 16.…”

“…In the latter, the AhR/ARNT complex binds to dioxin‐responsive elements (DREs) to induce transcription of target genes that encode drug‐metabolizing enzymes (eg, cytochrome P450 1A1) as well as proteins governing cell proliferation, differentiation, and apoptosis, which most likely facilitates carcinogenesis and tumor promotion 16. However, ARNT also forms a complex with AhR repressor (AhRR), which directly competes AhR/ARNT for binding to DREs and thus acts as a tumor suppressor 16. Moreover, ARNT might also promote survival and proliferation of tumor cells, independently of its roles in AhR and HIF signaling.…”

Breastfeeding duration modifies the effect of smoking during pregnancy on eczema from early childhood to adolescence

“…Experimental studies suggest that coal tar may improve the skin barrier by inducing the AHR (aryl-hydrocarbon receptor) gene [22]. Interestingly, cigarette smoke also influences the methylation of AHRR (aryl-hydrocarbon receptor repressor) [23] indicating a possible link between biological pathways influenced by cigarette smoke and those related to eczema. Existing studies report a protective effect of maternal gestational smoking for eczema in offspring [16, 18], null effects [24] and increased risks [3, 25].…”