Impact of cyclic hypoxia on HIF-1a regulation in endothelial cells – new insights for anti-tumor treatments

The transcription factor hypoxia inducible factor (HIF)-1 is a key regulator of the cellular response to hypoxia. HIF-1 consists of a constitutively expressed HIF-1b subunit and an inducible HIF-1a subunit [1– 4]. The main mechanism responsible for stabilization of HIF-1a is the inhibition of prolyl 4-hydroxylase domain (PHD) proteins, which hydroxylate the HIF-1a subunit in the presence of oxygen, leading to its sub-sequent ubiquitination and degradation [5]. Growth factors, in particular when their expression is driven by oncogenes, iron chelators and reactive oxygen species, are also reported to increase HIF-1a transcriptio