Aromatic Hydrocarbon Nuclear Translocator as a Common Component for the Hypoxia- and Dioxin-induced Gene Expression

Aromatic hydrocarbon nuclear translocator (Arnt) is an ubiquitously expressed protein that contains basic helix-loop-helix (bHLH) and Per-AhR-Arnt-Sim (PAS) motifs. Other bHLH-PAS proteins, hypoxia-inducible factor-1α (HIF-1α) and aromatic hydrocarbon receptor (AhR) mediate hypoxia- and dioxin-signal pathway, respectively. Arnt has been identified as a heterodimerization partner for AhR. AhR/Arnt heterodimer binds the regulatory region of xenobiotic-induced genes and activates their transcription. Here, in vivo results provide evidence that Arnt is involved in not only xenobiotic- but also hypoxia-induced transcriptional activation. In hypoxic condition, Arnt dimerizes with HIF-1α to make HIF-1α/Arnt heterodimer which is able to bind hypoxia-responsive DNA elements. The HIF-1α/Arnt heterodimer functions as a transactivator for hypoxia-inducible genes. Given that the expression of Arnt is limited, HIF-1α may compete with AhR for recruiting Arnt as a heteromeric partner. Consistent with this idea, the results indicate that the hypoxic activation of HIF-1α reduces dioxin-induced AhR's function on the dioxin-responsive reporter gene and the endogenous gene.