Hypoxia-inducible factor 1 (HIF1) is a heterodimeric transcription factor that plays a critical role in the cellular response to hypoxia. The HIF1 complex consists of two subunits, HIF-1a and HIF-1β, which are basic helix-loop-helix proteins of the PAS (Per, ARNT, Sim) family . HIF1 regulates the transcription of a broad range of genes that facilitate responses to the hypoxic environment, including genes regulating angiogenesis, erythropoiesis, cell cycle, metabolism and apoptosis. The widely expressed HIF-1a is typically degraded rapidly in normoxic cells by the ubiquitin/proteasomal pathway. Under normoxic conditions, HIF-1a is proline hydroxylated leading to a conformational change that promotes binding to the von Hippel Lindau protein (VLH) E3 ligase complex; ubiquitination and proteasomal degradation follows (3,4). Both hypoxic conditions and chemical hydroxylase inhibitors (such as desferrioxamine and cobalt) inhibit HIF-1a degradation and lead to its stabilization. In addition, HIF-1a can be induced in an oxygen-independent manner by various cytokines through the PI3K-AKT-mTOR pathway (5-7).HIF-1β is also known as AhR nuclear translocator (ARNT) due to its ability to partner with the aryl hydrocarbon receptor (AhR) to form a heterodimeric transcription factor complex . Together with AhR, HIF-1β plays an important role in xenobiotics metabolism .
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