Box 1.

Hypoxia-inducible Factors (HIFs).

HIF-1, HIF-2, and HIF-3 are heterodimeric transcription factors consisting of an oxygen-labile HIF-1α, HIF-2α, or HIF-3α monomer and a common stable β monomer.60,61 The labile monomers are continuously expressed and in normoxic conditions rapidly oxygen-dependently hydroxylated, ubiquitinated, and proteosomally degraded. They become stabilized in hypoxic conditions.61–64 This complex system enables rapid responses to hypoxic insults without the need for de novo protein synthesis. 61 When HIF-1α, HIF-2α, and HIF-3α become stabilized under hypoxic conditions, they translocate into the cell nucleus and heterodimerize with the stable β monomer (HIF-1β or ARNT) to become HIF-1, HIF-2, and HIF-3, respectively, and then bind to the hypoxia-responsive elements (HREs) of target genes.61–63 HIF-1 and HIF-2 are closely related and both activate HRE-dependent gene transcription. 63 Relatively little is known of the function of HIF-3. It is considered to be a negative regulator of HIF-1 and HIF-2 by competition for HIF-1β60,65 and plays a role in stroke-related diseases. 60 HIF-1 and HIF-2 are closely related but transcription of genes differs and HIF-2 is stable at higher oxygen concentrations than HIF-1. 61 HIF-1 is more acutely responsive to hypoxia, whereas HIF-2 is more chronically responsive.61,66 Moreover, HIF-1 induces preferentially transcription of genes of metabolic (glycolytic) enzymes, whereas HIF-2 induces preferentially angiogenesis-related gene transcription.62,67 Both HIF-1 and HIF-2 promote stemness of cells. 66 Downes et al. 61 analyzed which genes are transcriptionally regulated by HIF-1 and HIF-2 in primary human endothelial cells. HIF-1 induced expression of 700 genes, whereas HIF-2 induced expression of 1450 genes of which 300 genes were transcriptionally activated by both HIF-1 and HIF-2. 61 An alternative explanation for the differences in expression patterns regulated by HIF-1 and HIF-2 is a difference in cell types in which HIF-1 and HIF-2 are active. 63 Indeed, we have observed differences in expression levels of HIF-2α and HIF-1α in GSCs and endothelial cells of arterioles, respectively.9,19 Inhibitors of HIF-1 and HIF-2 have been discussed recently for their potential use to target therapeutically cancer stem cells. 68

Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; GSCs, glioblastoma stem cells.