Regulatory crosstalk and interference between the xenobiotic and hypoxia sensing pathways at the AhR-ARNT-HIF1α signaling node

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates many of the responses to toxic environmental chemicals such as TCDD or dioxin-like PCBs. To regulate gene expression, the AhR requires its binding partner, the aryl hydrocarbon receptor nuclear translocator (ARNT). ARNT is also required by the hypoxia-inducible factor-1α (HIF-1α), a crucial regulator of responses to conditions of reduced oxygen. The important role of ARNT in both the AhR and HIF-1α signaling pathways establishes a meaningful foundation for a possible crosstalk between these two vitally important signaling pathways. This crosstalk might lead to interference between the two signaling pathways and thus might play a role in the variety of cellular responses after exposure to AhR ligands and reduced oxygen availability. This review focuses on studies that have analyzed the effect of low oxygen environments and hypoxiamimetic agents on AhR signaling and conversely, the effect of AhR ligands, with a special emphasis on PCBs, on HIF-1α signaling. We highlight studies that assess the role of ARNT, elucidate the mechanism of the crosstalk, and discuss the physiological implications for exposure to AhR-inducing compounds in the context of hypoxia.

A HIF-1α-driven feed-forward loop augments HIF signalling in Hep3B cells by upregulation of ARNT

“…In addition to its role in the HIF pathway, ARNT is a key player in the Aryl hydrocarbon receptor (AhR) signalling pathway, which is activated by chemical compounds. 16, 36 An antagonistic crosstalk between AhR and HIF signalling via ARNT has been established but whether there is a competition for ARNT is unclear. 36 Early evidence for such an antagonism was reported by Gradin et al 37 However, the results of our study support the concept of ARNT as being a limiting factor in HIF signalling.…”

“…16, 36 An antagonistic crosstalk between AhR and HIF signalling via ARNT has been established but whether there is a competition for ARNT is unclear. 36 Early evidence for such an antagonism was reported by Gradin et al 37 However, the results of our study support the concept of ARNT as being a limiting factor in HIF signalling. Whether an increased ARNT level facilitates xenobiotic responses in hypoxia needs to be evaluated.…”

Air pollution and allergic diseases

“…Ahr signaling requires dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), also known as hypoxia-inducible factor beta (HIF1β). Accordingly, a crosstalk between the hypoxia-inducible factor 1-alpha (HIF1α) and Ahr pathways has been proposed, as both might compete for ARNT binding (94). In T-cells, HIF1α driven glycolysis supports T H 17 differentiation by promoting expression of RORγt, whereas in conditions supporting T REG differentiation HIF1α favors Foxp3 induction (95, 96).…”

Is tryptophan metabolism involved in sleep apnea-related cardiovascular co-morbidities and cancer progression?

“…Indeed, ARNT, the binding partner required by AhR to regulate gene expression, was also required by HIF-1a [111]. Hypoxia can thus inhibit AhR activation [112], probably by competing for heterodimer formation with the ARNT, the same way by which AhRR represses the transcription activity of AhR [92].…”