HIF3α: the little we know

Hypoxia-inducible factors (HIFs) are key regulators of the transcriptional response to hypoxic stress. Three inducible isoforms of HIF are present in mammals. HIF1 alpha and HIF2 alpha are the best characterized and structurally similar isoforms, while HIF3 alpha is the most distantly related and is less studied. The HIF3 alpha gene undergoes complex regulation and produces a large number of long and short mRNA splice variants, which are translated into different polypeptides. These molecules primarily act as negative regulators of HIF1 alpha and HIF2 alpha activity and transcriptional activators of target genes, according to the variant and the biological context. The present review provides an overview of the available, fragmented and sometimes contradictory information concerning the structure, expression and distinct roles of the HIF3 alpha variants, in both hypoxic adaptation and in hypoxia-unrelated activities. The pathological consequences of HIF3 alpha deregulation are also illustrated.