HAF : the new player in oxygen-independent HIF-1alpha degradation

Adaptation to hypoxia is primarily mediated by the hypoxia-inducible transcription factor, HIF. The regulation of HIF activity by the oxygen-dependent degradation of the HIF-1alpha and HIF-2alpha subunits by the pVHL E3 ligase complex has been well characterized. We have recently described the hypoxia-associated factor, HAF, as an E3 ligase for HIF-1alpha that does not degrade HIF-2alpha. Here we summarize the mechanism of HAF-mediated HIF-1alpha degradation and the importance of oxygen-independent HIF-1alpha regulation in cancer. We also discuss the implications of the new HAF: HIF-1alpha degradation pathway with respect to other novel mediators of oxygen-independent HIF-alpha degradation. Finally, we review the significance of HAF as an isoform-specific E3 ligase in light of new information on the non-overlapping functions of HIF-1alpha and HIF-2alpha in cancer.