Hypoxia-Inducible Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) (HIF-1β): Is It a Rare Exception?

The aryl hydrocarbon receptor nuclear translocator (ARNT), also designated as hypoxia-inducible factor (HIF)-1 beta, 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-alpha subunits. HIF-alpha 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-1 beta). 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 anticancer 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.