Figure 1

The aryl hydrocarbon receptor nuclear translocator. (A) ARNT interconnects the HIF and AhR pathway. Under sufficient oxygen supply (normoxia), HIF-1α is hydroxylated at two conserved proline residues within its oxygen-dependent degradation domain (ODD) by prolylhydroxylase domain (PHD) enzymes. This posttranslational modification is recognized by the von Hippel-Lindau (VHL) tumor suppressor protein leading to ubiquitination and proteasomal degradation of HIF-1α. Asparaginyl hydroxylation residue within the C-terminal transactivation domain (TAD) of HIF-1α catalyzed by factor inhibiting HIF (FIH) prevents the recruitment of cofactors required for target gene expression. Hypoxia inhibits both PHD and FIH, thus leading to HIF-1α accumulation and nuclear translocation. Heterodimerization of HIF-1α and ARNT is mediated by PAS domains. Subsequently, the HIF-1α/ARNT complex (HIF-1) initiates target gene expression in conjunction with cofactors (that is, CBP/p300; not shown) (3). By contrast, the AhR pathway is activated by environmental pollutants (for example, dioxin exposure), leading to nuclear translocation of AhR. Subsequently, AhR/ARNT complexes initiate the expression of target genes such as monooxygenases (7). ARNT is regarded as constitutively expressed but can be upregulated in response to hypoxia in a cell-specific manner (dotted arrow; see text for details). HRE, hypoxia responsive element; NPC, nuclear pore complex; VEGF, vascular endothelial growth factor; XRE, xenobiotic responsive element. (B) Proposed concept of hypoxia-dependent upregulation of ARNT and associated research questions.