Hypoxia-inducible aryl hydrocarbon receptor nuclear translocator (ARNT) (HIF-1β): is it a rare exception?

Abstract

The aryl hydrocarbon receptor nuclear translocator (ARNT), also designated as hypoxia-inducible factor (HIF)-1β, plays a pivotal role in the adaptive responses to (micro-)environmental stresses such as dioxin exposure and oxygen deprivation (hypoxia). ARNT belongs to the group of basic helix-loop-helix (bHLH)-Per-ARNT-Sim (PAS) transcription factors, which act as heterodimers. ARNT serves as a common binding partner for the aryl hydrocarbon receptor (AhR) as well as HIF-α subunits. HIF-α proteins are regulated in an oxygen-dependent manner, whereas ARNT is generally regarded as constitutively expressed, meaning that neither the arnt mRNA nor the protein level is influenced by hypoxia (despite the name HIF-1β). However, there is emerging evidence that tumor cells derived from different entities are able to upregulate ARNT, especially under low oxygen tension in a cell-specific manner. The objective of this review is therefore to highlight and summarize current knowledge regarding the hypoxia-dependent upregulation of ARNT, which is in sharp contrast to the general point of view described in the literature. Elucidating the mechanism behind this rare cellular attribute will help us to gain new insights into HIF biology and might provide new strategies for anti-cancer therapeutics. In conclusion, putative treatment effects on ARNT should be taken into account while studying the HIF pathway. This step is of great importance when ARNT is intended to serve as a loading control or as a reference.

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.

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.